lnu.sePublications
Change search
Refine search result
12 1 - 50 of 97
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Freire, Thales Souza
    et al.
    Univ Sao Paulo, Brazil.
    Zukerman-Schpector, Julio
    Univ Fed Sao Carlos, Brazil.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Caracelli, Ignez
    Univ Fed Sao Carlos, Brazil.
    Structural and thermodynamic characterization of allosteric transitions in human serum albumin with metadynamics simulations2024In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 26, no 7, p. 6436-6447Article in journal (Refereed)
    Abstract [en]

    Human serum albumin (HSA) is the most prominent protein in blood plasma, responsible for the maintenance of blood viscosity and transport of endogenous and exogenous molecules. Fatty acids (FA) are the most common ligands of HSA and their binding can modify the protein's structure. The protein can assume two well-defined conformations, referred to as 'Neutral' and 'Basic'. The Neutral (N) state occurs at pH close to 7.0 and in the absence of bound FA. The Basic (B) state occurs at pH higher than 8.0 or when the protein is bound to long-chain FA. HSA's allosteric behaviour is dependent on the number on FA bound to the structure. However, the mechanism of this allosteric regulation is not clear. To understand how albumin changes its conformation, we compared a series of HSA structures deposited in the protein data bank to identify the minimum amount of FA bound to albumin, which is enough to drive the allosteric transition. Thereafter, non-biased molecular dynamics (MD) simulations were used to track protein's dynamics. Surprisingly, running an ensemble of relatively short MD simulations, we observed rapid transition from the B to the N state. These simulations revealed differences in the mobilities of the protein's subdomains, with one domain unable to fully complete its transition. To track the transition dynamics in full, we used these results to choose good geometrical collective variables for running metadynamics simulations. The metadynamics calculations showed that there was a low energy barrier for the transition from the B to the N state, while a higher energy barrier was observed for the N to the B transition. These calculations also offered valuable insights into the transition process. Human serum albumin (HSA) is an allosteric protein that can change conformation state through low energy barriers, being the most prominent protein in blood plasma, responsible for the maintenance of blood viscosity and transport of endogenous and exogenous molecules.

  • 2.
    Yang, Jingmei
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Synergy and antagonism between azacitidine and FLT3 inhibitors2024In: Computers in Biology and Medicine, ISSN 0010-4825, E-ISSN 1879-0534, Vol. 169, p. 107889-107889, article id 107889Article in journal (Refereed)
    Abstract [en]

    Synergetic interactions between drugs can make a drug combination more effective. Alternatively, they may allow to use lower concentrations and thus avoid toxicities or side effects that not only cause discomfort but might also reduce the overall survival. Here, we studied whether synergy exists between agents that are used for treatment of acute myeloid leukaemia (AML). Azacitidine is a demethylation agent that is used in the treatment of AML patients that are unfit for aggressive chemotherapy. An activating mutation in the FLT3 gene is common in AML patients and in the absence of specific treatment makes prognosis worse. FLT3 inhibitors may be used in such cases. We sought to determine whether combination of azacitidine with a FLT3 inhibitor (gilteritinib, quizartinib, LT-850-166, FN-1501 or FF-10101) displayed synergy or antagonism. To this end, we calculated dose–response matrices of these drug combinations from experiments in human AML cells and subsequently analysed the data using a novel consensus scoring algorithm. The results show that combinations that involved non-covalent FLT3 inhibitors, including the two clinically approved drugs gilteritinib and quizartinib were antagonistic. On the other hand combinations with the covalent inhibitor FF-10101 had some range of concentrations where synergy was observed.

    Download full text (pdf)
    fulltext
  • 3.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The Emerging Role of Molecular Dynamics Simulations in Cancer Research2024In: Comprehensive Computational Chemistry: Molecular Dynamics Simulations and Reaction Rates / [ed] Yanez, Manuel and Boyd, Russell J., Oxford. UK: Elsevier, 2024, p. 910-920Chapter in book (Refereed)
    Abstract [en]

    Cancers ultimately develop due to aberrations that involve proteins and modify their effects. Given that the structures of many proteinsinvolved in cancer pathogenesis are known, numerous studies have employed MD simulations in cancer research. In this chapter, somecauses and treatments for cancer are briefly introduced. Thereafter, systems where cancer development or therapy have been studied byMD simulations are described, focusing on contemporary subjects of interest. These include tumor cell metabolism, RAS proteins,driver mutations, allosteric inhibitors, kinetics of drug binding, activation of protein kinases and anticancer drug delivery. While notproviding a complete picture of the fields, these subjects allow the reader to understand what sorts of systems are studied, how, andwhich conclusions can be made with the help of MD simulations. This might help the interested reader to utilize such simulations forfurther studies in the field.

  • 4.
    Yang, Jingmei
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Combination strategies to overcome drug resistance in FLT+ acute myeloid leukaemia2023In: Cancer Cell International, E-ISSN 1475-2867, Vol. 23, no 1, article id 161Article in journal (Refereed)
    Abstract [en]

    BackgroundAcute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly.MethodsWe examined combination therapies aimed at FLT3(+)-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism.ResultsWe show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance.ConclusionsThis study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.

  • 5.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Estimating the Gibbs Hydration Energies of Actinium and Trans-Plutonium Actinides2023In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 24, no 2, article id e202200516Article in journal (Refereed)
    Abstract [en]

    The use of actinides for medical, scientific and technological purposes has gained momentum in the recent years. This creates a need to understand their interactions with biomolecules, both at the interface and as they become complexed. Calculation of the Gibbs binding energies of the ions to biomolecules, i. e., the Gibbs energy change associated with a transfer of an ion from the water phase to its binding site, could help to understand the actinides' toxicities and to design agents that bind them with high affinities. To this end, there is a need to obtain accurate reference values for actinide hydration, that for most actinides are not available from experiment. In this study, a set of ionic radii is developed that enables future calculations of binding energies for Pu3+ and five actinides with renewed scientific and technological interest: Ac3+, Am3+, Cm3+, Bk3+ and Cf3+. Reference hydration energies were calculated using quantum chemistry and ion solvation theory and agree well for all ions except Ac3+, where ion solvation theory seems to underestimate the magnitude of the Gibbs hydration energy. The set of radii and reference energies that are presented here provide means to calculate binding energies for actinides and biomolecules.

    Download full text (pdf)
    fulltext
  • 6.
    Meelua, Wijitra
    et al.
    Univ Phayao, Thailand.
    Wanjai, Tanchanok
    Univ Phayao, Thailand.
    Thinkumrob, Natechanok
    Univ Phayao, Thailand.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jitonnom, Jitrayut
    Univ Phayao, Thailand.
    Multiscale QM/MM Simulations Identify the Roles of Asp239 and 1‑OH···Nucleophile in Transition State Stabilization in Arabidopsis thaliana Cell-Wall Invertase 12023In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 63, no 15, p. 4827-4838Article in journal (Refereed)
    Abstract [en]

    Arabidopsis thaliana cell-wallinvertase1 (AtCWIN1), a key enzyme in sucrose metabolism in plants, catalyzesthe hydrolysis of sucrose into fructose and glucose. AtCWIN1 belongsto the glycoside hydrolase GH-J clan, where two carboxylate residues(Asp23 and Glu203 in AtCWIN1) are well documented as a nucleophileand an acid/base catalyst. However, details at the atomic level aboutthe role of neighboring residues and enzyme-substrate interactionsduring catalysis are not fully understood. Here, quantum mechanical/molecularmechanical (QM/MM) free-energy simulations were carried out to clarifythe origin of the observed decreased rates in Asp239Ala, Asp239Asn,and Asp239Phe in AtCWIN1 compared to the wild type and delineate therole of Asp239 in catalysis. The glycosylation and deglycosylationsteps were considered in both wild type and mutants. Deglycosylationis predicted to be the rate-determining step in the reaction, witha calculated overall free-energy barrier of 15.9 kcal/mol, consistentwith the experimental barrier (15.3 kcal/mol). During the reaction,the -1 furanosyl ring underwent a conformational change correspondingto E-3 & LRARR; [E-2](⧧) & LRARR; E-1 according to the nomenclature of saccharide structures alongthe full catalytic reaction. Asp239 was found to stabilize not onlythe transition state but also the fructosyl-enzyme intermediate, whichexplains findings from previous structural and mutagenesis experiments.The 1-OH & BULL;& BULL;& BULL;nucleophile interaction has been found toprovide an important contribution to the transition state stabilization,with a contribution of & SIM;7 kcal/mol, and affected glycosylationmore significantly than deglycosylation. This study provides molecularinsights that improve the current understanding of sucrose bindingand hydrolysis in members of clan GH-J, which may benefit proteinengineering research. Finally, a rationale on the sucrose inhibitorconfiguration in chicory 1-FEH IIa, proposed a long time ago in theliterature, is also provided based on the QM/MM calculations.

  • 7.
    Månsson, Alf
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ušaj, Marko
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Moretto, Luisa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Matusovsky, Oleg
    McGill Univ, Canada.
    Velayuthan, Lok Priya
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rassier, Dilson E.
    McGill Univ, Canada.
    New paradigms in actomyosin energy transduction: Critical evaluation of non-traditional models for orthophosphate release2023In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 45, no 9, article id 2300040Article in journal (Refereed)
    Abstract [en]

    Release of the ATP hydrolysis product ortophosphate (Pi) from the active site of myosin is central in chemo-mechanical energy transduction and closely associated with the main force-generating structural change, the power-stroke. Despite intense investigations, the relative timing between Pi-release and the power-stroke remains poorly understood. This hampers in depth understanding of force production by myosin in health and disease and our understanding of myosin-active drugs. Since the 1990s and up to today, models that incorporate the Pi-release either distinctly before or after the power-stroke, in unbranched kinetic schemes, have dominated the literature. However, in recent years, alternative models have emerged to explain apparently contradictory findings. Here, we first compare and critically analyze three influential alternative models proposed previously. These are either characterized by a branched kinetic scheme or by partial uncoupling of Pi-release and the power-stroke. Finally, we suggest critical tests of the models aiming for a unified picture.

  • 8.
    Freire, Thales Souza
    et al.
    Univ Fed Sao Carlos, Brazil.
    Caracelli, Ignez
    Univ Fed Sao Carlos, Brazil.
    Zukerman-Schpector, Julio
    Univ Fed Sao Carlos, Brazil.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Resistance to a tyrosine kinase inhibitor mediated by changes to the conformation space of the kinase2023In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 25, no 8, p. 6175-6183Article in journal (Refereed)
    Abstract [en]

    Gilteritinib is a highly selective and effective inhibitor of the FLT3/ITD mutated protein, and is used successfully in treating acute myeloid leukaemia (AML). Unfortunately, tumour cells gradually develop resistance to gilteritinib due to mutations in the molecular drug target. The atomistic details behind this observed resistance are not clear, since the protein structure of the complex is only available in the inactive state, while the drug binds better to the active state. To overcome this limitation, we used a computer-aided approach where we docked gilteritinib to the active site of FLT3/ITD and calculated the Gibbs free energy difference between the binding energies of the parental and mutant enzymes. These calculations agreed with experimental estimations for one mutation (F691L) but not the other (D698N). To further understand how these mutations operate, we used metadynamics simulations to study the conformational landscape of the activation process. Both mutants show a lower activation energy barrier which suggests that they are more likely to adopt an active state until inhibited, making the mutant enzymes more active. This suggests that a higher efficiency of tyrosine kinases contributes to resistance not only against type 2 but also against type 1 kinase inhibitors.

  • 9.
    Xu, Yuan
    et al.
    Xiamen Univ, China.
    Zhang, Shu
    Xiamen Univ, China.
    Lindahl, Erik
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Wu, Wei
    Xiamen Univ, China.
    Su, Peifeng
    Xiamen Univ, China.
    A general tight-binding based energy decomposition analysis scheme for intermolecular interactions in large molecules2022In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 157, no 3, article id 034104Article in journal (Refereed)
    Abstract [en]

    In this work, a general tight-binding based energy decomposition analysis (EDA) scheme for intermolecular interactions is proposed. Different from the earlier version [Xu et al., J. Chem. Phys. 154, 194106 (2021)], the current tight-binding based density functional theory (DFTB)-EDA is capable of performing interaction analysis with all the self-consistent charge (SCC) type DFTB methods, including SCC-DFTB2/3 and GFN1/2-xTB, despite their different formulas and parameterization schemes. In DFTB-EDA, the total interaction energy is divided into frozen, polarization, and dispersion terms. The performance of DFTB-EDA with SCC-DFTB2/3 and GFN1/2-xTB for various interaction systems is discussed and assessed. Published under an exclusive license by AIP Publishing.

  • 10.
    Oruganti, Baswanth
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lindahl, Erik
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Yang, Jingmei
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Amiri, Wahid
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rahimullah, Rezwan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Allosteric enhancement of the BCR-Abl1 kinase inhibition activity of nilotinib by cobinding of asciminib2022In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 298, no 8, article id 102238Article in journal (Refereed)
    Abstract [en]

    Inhibitors that bind competitively to the ATP binding pocket in the kinase domain of the oncogenic fusion protein BCR-Abl1 are used successfully in targeted therapy of chronic myeloid leukemia (CML). Such inhibitors provided the first proof of concept that kinase inhibition can succeed in a clinical setting. However, emergence of drug resistance and dose-dependent toxicities limit the effectiveness of these drugs. Therefore, treatment with a combination of drugs without overlapping resistance mechanisms appears to be an appropriate strategy. In the present work, we explore the effectiveness of combination therapies of the recently developed allosteric inhibitor asciminib with the ATP-competitive inhibitors nilotinib and dasatinib in inhibiting the BCR-Abl1 kinase activity in CML cell lines. Through these experiments, we demonstrate that asciminib significantly enhances the inhibition activity of nilotinib, but not of dasatinib. Exploring molecular mechanisms for such allosteric enhancement via systematic computational investigation incorporating molecular dynamics, metadynamics simulations, and density functional theory calculations, we found two distinct contributions. First, binding of asciminib triggers conformational changes in the inactive state of the protein, thereby making the activation process less favorable by similar to 4 kcal/mol. Second, the binding of asciminib decreases the binding free energies of nilotinib by similar to 3 and similar to 7 kcal/mol for the wildtype and T315I-mutated protein, respectively, suggesting the possibility of reducing nilotinib dosage and lowering risk of developing resistance in the treatment of CML.

    Download full text (pdf)
    fulltext
  • 11.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Computational studies of protein–drug binding affinity changes upon mutations in the drug target2022In: Wiley Interdisciplinary Reviews. Computational Molecular Science, ISSN 1759-0876, E-ISSN 1759-0884, Vol. 12, no 1, article id e1563Article in journal (Refereed)
    Abstract [en]

    Mutations that lead to drug resistance limit the efficacy of antibiotics, antiviral drugs, targeted cancer therapies, and other treatments. Accurately calculating protein–drug binding affinity changes upon mutations in the drug target is of high interest as this can yield a better understanding into how such mutations drive drug-resistance, especially when the mutation in question does not directly interfere with binding of the drug. The main aim of this article is to provide an up-to-date reference on the computational tools that are available for the calculation of Gibbs energy (free energy) changes upon mutation, their strengths, and limitations. The methods that are discussed include free energy calculations (free energy perturbation, thermodynamic integration, multistate Bennett acceptance ratio), analysis of molecular dynamics simulations (linear interaction energy, molecular mechanics [MM]/Poisson–Boltzmann solvated area, and MM/generalized Born solvated area), and methods that involve quantum mechanical calculations (including QM/MM). The possibility to use machine learning is also introduced. Given that the benefit of accurately calculating binding affinity changes upon mutation depends on comparing calculated values with experimental measurements, a brief survey on experimental methods and observables is provided. Examples of computational studies that go beyond calculating the Gibbs energy changes are given. Factors that need to be addressed by the computational chemist and potential pitfalls are discussed at length.

    Download full text (pdf)
    fulltext
  • 12.
    Moretto, Luisa
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ušaj, Marko
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Matusovsky, Oleg
    McGill Univ, Canada.
    Rassier, Dilson E.
    McGill Univ, Canada.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Multistep orthophosphate release tunes actomyosin energy transduction2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 4575Article in journal (Refereed)
    Abstract [en]

    Release of the ATP hydrolysis product orthophosphate (Pi) from the myosin active site is central in force generation but is poorly understood. Here, Moretto et al. present evidence for multistep Pi-release reconciling apparently contradictory results. Muscle contraction and a range of critical cellular functions rely on force-producing interactions between myosin motors and actin filaments, powered by turnover of adenosine triphosphate (ATP). The relationship between release of the ATP hydrolysis product ortophosphate (Pi) from the myosin active site and the force-generating structural change, the power-stroke, remains enigmatic despite its central role in energy transduction. Here, we present a model with multistep Pi-release that unifies current conflicting views while also revealing additional complexities of potential functional importance. The model is based on our evidence from kinetics, molecular modelling and single molecule fluorescence studies of Pi binding outside the active site. It is also consistent with high-speed atomic force microscopy movies of single myosin II molecules without Pi at the active site, showing consecutive snapshots of pre- and post-power stroke conformations. In addition to revealing critical features of energy transduction by actomyosin, the results suggest enzymatic mechanisms of potentially general relevance.

    Download full text (pdf)
    fulltext
  • 13.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rotating between ponatiniband imatinib temporarily increasesthe efficacy of imatinib as shownin a chronic myeloid leukaemiamodel2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 5164Article in journal (Refereed)
    Abstract [en]

    Targeted therapies for chronic myeloid leukaemia (CML) are effective, but rarely curative. Patients typically require treatment indefinitely, which gives ample time for drug resistance to evolve. Drug resistance issues are one of the main causes of death owing to CML, thus any means of preventing resistance are of importance. Drug rotations, wherein treatment is switched periodically between different drugs are one such option, and have been theorized to delay the onset of resistance. In vitro testing of drug rotation therapy is a first step towards applying it in animal or human trials. We developed a method for testing drug rotation protocols in CML cell lines based around culturing cells with a moderate amount of inhibitors interspersed with washing procedures and drug swaps. Drug rotations of imatinib and ponatinib were evaluated in a CML specific cell line, KCL-22. The growth of KCL-22 cells was initially reduced by a drug rotation, but the cells eventually adapted to the protocol. Our results show that ponatinib in a drug rotation temporarily sensitizes the cells to imatinib, but the effect is short-lived and is eventually lost after a few treatment cycles. Possible explanations for this observation are discussed.

    Download full text (pdf)
    fulltext
  • 14.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The molecular mechanisms behind activation of FLT3 in acute myeloid leukemia and resistance to therapy by selective inhibitors2022In: Biochimica et Biophysica Acta. CR. Reviews on Cancer, ISSN 0304-419X, E-ISSN 1879-2561, Vol. 1877, no 1, article id 188666Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia is an aggressive cancer, which, in spite of increasingly better understanding of its genetic background remains difficult to treat. Mutations in the FLT3 gene are observed in ≈30% of the patients. Most of these mutations are internal tandem duplications (ITDs) of a sequence within the protein coding region, an activation mechanism that is almost non-existent with other genes and cancers. As patients each carry their own unique set of mutations, it is challenging to understand how ITDs activate the protein, and ascertain the risk for each individual patient. Available treatment options are limited due to development of drug resistance. Here, recent studies are reviewed that help to better understand the molecular mechanism behind activation of the FLT3 protein due to mutations. It is argued that difference in mutation sequences and especially location might be coupled to prognosis. When it comes to FLT3 inhibitors, key differences between them can be attributed to the mode of inhibition (type-1 and type-2 inhibitors), effective inhibitory coefficient in the blood plasma and off-target binding. Accounting for the position and length of insertions may in the future be used to predict prognosis and rationalise treatment. Development of new inhibitors must take into account the potential for resistance mutations. Inhibitors aimed at multiple specific targets are currently being developed. These, and as well as combination therapies will hopefully lead to longer periods during which targeted FLT3 therapy will remain effective.

    Download full text (pdf)
    fulltext
  • 15.
    Oruganti, Baswanth
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Activation of Abl1 Kinase Explored Using Well-Tempered Metadynamics Simulations on an Essential Dynamics Sampled Path2021In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 17, no 11, p. 7260-7270Article in journal (Refereed)
    Abstract [en]

    Well-tempered metadynamics (wT-metaD) simulations using path collective variables (CVs) have been successfully applied in recent years to explore conformational transitions in protein kinases and other biomolecular systems. While this methodology has the advantage of describing the transitions with a limited number of predefined path CVs, it requires as an input a reference path connecting the initial and target states of the system. It is desirable to automate the path generation using approaches that do not rely on the choice of geometric CVs to describe the transition of interest. To this end, we developed an approach that couples essential dynamics sampling with wT-metaD simulations. We used this newly developed procedure to explore the activation mechanism of Abl1 kinase and compute the associated free energy barriers. Through these simulations, we identified a three-step mechanism for the activation that involved two metastable intermediates that possessed a partially open activation loop and differed primarily in the "in" or "out" conformation of the aspartate residue of the DFG motif. One of these states is similar to a conformation that was detected in previous spectroscopic studies of Abl1 kinase, albeit its mechanistic role in the activation was hitherto not well understood. The present study establishes its intermediary role in the activation and predicts a rate-determining free energy barrier of 13.8 kcal/mol that is in good agreement with previous experimental and computational estimates. Overall, our study demonstrates the usability of essential dynamics sampling as a path CV in wT-metaD to conveniently study conformational transitions and accurately calculate the associated barriers.

  • 16.
    Yang, Jingmei
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lindström, Jonathan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Combating drug resistance in acute myeloid leukaemia by drug rotations: the effects of quizartinib and pexidartinib2021In: Cancer Cell International, E-ISSN 1475-2867, Vol. 21, no 1, article id 198Article in journal (Refereed)
    Abstract [en]

    Background Acute myeloid leukaemia (AML) is an aggressive blood cancer. In approximately 30% of the cases, driver mutations in the FLT3 gene are identified. FLT3 inhibitors are used in treatment of such patients together with cytotoxic drugs or (in refractory AML) as single agents. Unfortunately, resistance to FLT3 inhibitors limits their efficacy. Resistance is often due to secondary mutations in the gene encoding the molecular target. The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations. In chronic myeloid leukaemia (CML), it has been suggested that rotation between drugs with a different landscape of resistance mutations might postpone the emergence of resistance. Methods We studied the effect of quizartinib and pexidartinib in AML cell lines that express FLT3 (MOLM-14 and MV4-11). Using a rotation protocol, we further examined whether the emergence of resistance could be postponed. Computational modelling was used to analyse the onset of resistance and suggest which mutations are most likely to occur in a quantitative fashion. Results The cells were sensitive to both inhibitors but quickly developed resistance that could be inherited, suggesting a genetic origin. Rotation protocols were not useful to postpone the emergence of resistance, which implies that such protocols, or changing from pexidartinib to quizartinib (or vice-versa) should not be used in patients. The computational modelling led to similar conclusions and suggested that F691L is the most common mutation to occur with quizartinib, and also when both drugs are used in rotation. Conclusions AML patients are not likely to benefit from a quizartinib/pexidartinib rotation protocol. A combination of tyrosine kinase inhibitors (with different molecular targets) might be more useful in the future. Development of specific FLT3 inhibitors that are less sensitive to resistance mutations might also lead to a better outcome.

  • 17.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Preferential Binding of Lanthanides to Methanol Dehydrogenase Evaluated with Density Functional Theory2021In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 125, no 9, p. 2251-2257Article in journal (Refereed)
    Abstract [en]

    Methanol dehydrogenase (MDH) is an enzyme used by certain bacteria for the oxidation of methanol to formaldehyde, which is a necessary metabolic reaction. The discovery of a lanthanide-dependent MDH reveals that lanthanide ions (Ln(3+)) have a role in biology. Two types of MDH exist in methane-utilizing bacteria: one that is Ca2+-dependent (MxaF) and another that is Ln(3+)-dependent. Given that the triply charged Ln(3+) are strongly hydrated, it is not clear how preference for Ln(3+) is manifested and if the Ca2+-dependent MxaF protein can also bind Ln(3+) ions. A computational approach was used to estimate the Gibbs energy differences between the binding of Ln(3+) and Ca2+ to MDH using density functional theory. The results show that both proteins bind La3+ with higher affinity than Ca2+, albeit with a more pronounced difference in the case of Ln(3+)-dependent MDH. Interestingly, the binding of heavier lanthanides is preferred over the binding of La3+, with Gd3+ showing the highest affinity for both proteins of all Ln(3+) ions that were tested (La3+, Sm3+, Gd3+, Dy3+, and Lu3+). Energy decomposition analysis reveals that the higher affinity of La3+ than Ca2+ to MDH is due to stronger contributions of electrostatics and polarization, which overcome the high cost of desolvating the ion.

  • 18.
    Xu, Yuan
    et al.
    Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, China;Xiamen University, China.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Wu, Wei
    Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, China;Xiamen University, China.
    Su, Peifeng
    Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, China;Xiamen University, China.
    Understanding intermolecular interactions of large systems in ground state and excited state by using density functional based tight binding methods2021In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 154, no 19, article id 194106Article in journal (Refereed)
    Abstract [en]

    A novel energy decomposition analysis scheme, named DFTB-EDA, is proposed based on the density functional based tight-binding method (DFTB/TD-DFTB), which is a semi-empirical quantum mechanical method based on Kohn–Sham-DFT for large-scale calculations. In DFTB-EDA, the total interaction energy is divided into three terms: frozen density, polarization, and dispersion. Owing to the small cost of DFTB/TD-DFTB, DFTB-EDA is capable of analyzing intermolecular interactions in large molecular systems containing several thousand atoms with high computational efficiency. It can be used not only for ground states but also for excited states. Test calculations, involving the S66 and L7 databases, several large molecules, and non-covalent bonding complexes in their lowest excited states, demonstrate the efficiency, usefulness, and capabilities of DFTB-EDA. Finally, the limits of DFTB-EDA are pointed out.

    Download full text (pdf)
    accepted_manuscript
  • 19.
    Georgoulia, Panagiota S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Gothenburg, Sweden.
    Bjelic, Sinisa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Deciphering the molecular mechanism of FLT3 resistance mutations2020In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 287, no 15, p. 3200-3220Article in journal (Refereed)
    Abstract [en]

    FMS-like tyrosine kinase 3 (FLT3) has been found to be mutated in 30% of acute myeloid leukaemia patients. Small-molecule inhibitors targeting FLT3 that are currently approved or still undergoing clinical trials are subject to drug resistance due to FLT3 mutations. How these mutations lead to drug resistance is hitherto poorly understood. Herein, we studied the molecular mechanism of the drug resistance mutations D835N, Y842S and M664I, which confer resistance against the most advanced inhibitors, quizartinib and PLX3397 (pexidartinib), using enzyme kinetics and computer simulations. In vitro kinase assays were performed to measure the comparative catalytic activity of the native protein and the mutants, using a bacterial expression system developed to this aim. Our results reveal that the differential drug sensitivity profiles can be rationalised by the dynamics of the protein-drug interactions and perturbation of the intraprotein contacts upon mutations. Drug binding induced a single conformation in the native protein, whereas multiple conformations were observed otherwise (in the mutants or in the absence of drugs). The end-point kinetics measurements indicated that the three resistant mutants conferred catalytic activity that is at least as high as that of the reference without such mutations. Overall, our calculations and measurements suggest that the structural dynamics of the drug-resistant mutants that affect the active state and the increased conformational freedom of the remaining inactive drug-bound population are the two major factors that contribute to drug resistance in FLT3 harbouring cancer cells. Our results explain the mechanism of drug resistance mutations and can aid to the design of more effective tyrosine kinase inhibitors.

  • 20.
    Houshmand, F.
    et al.
    K.N. Toosi University of technology, Iran;Technical and Vocational University, Iran.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Jalili, S.
    K.N. Toosi University of technology, Iran.
    Schofield, J.
    University of Toronto, Canada.
    Exciton effect in new generation of carbon nanotubes: graphdiyne nanotubes2020In: Journal of Molecular Modeling, ISSN 1610-2940, E-ISSN 0948-5023, Vol. 26, no 7, p. 1-10, article id 171Article in journal (Refereed)
    Abstract [en]

    Graphdiyne-based nanotubes (GDNTs) are a novel type of carbon nanotubes. While conventional carbon nanotubes (CNTs) aregenerated by rolling graphene sheets, GDNTs are generated by rolling sheets that are similar to graphene but where the edges areelongated by the introduction of additional acetylene bonds between vertices (C6 aromatic rings). Such nanotubes are predicted tohave many useful practical applications, but a thorough understanding of the relationship between their structure and theirphysical properties is still missing. We present a theoretical study of the electronic and optical properties of GDNTs. Thestructural, electronic, and optical properties of GDNTs with different diameters (i.e., 2–10 additional acetylene bonds) havebeen studied systematically by using density function theory (DFT) and self-consistent charge density functional tight-binding(SCC-DFTB) and by solving the Bethe–Salpeter equation (BSE), with and without considering the electron-hole interactions.The results indicate that the GDNTs are semiconductors with the direct band gap in close range, which is beneficial forphotoelectronic devices and applications. Moreover, the absorption spectra of the GDNTs with different edge structures, (armchair,and zigzag) revealed little differences between the optical spectra of armchair and zigzag GDNTs, which could mean thatfine separation between those structures (a process that is likely difficult and expensive in practice) will not be necessary.Importantly, the nanotubes were highly stable based on their cohesive energies, and their exciton binding energies were as largeas about ~ 1 eV. From a methodological point of view, SCC-DFTB was found to be in agreement with more elaborate DFTcalculations for most systems.

  • 21.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Inferring time-dependent population growth rates in cell cultures undergoing adaptation2020In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 21, no 1, p. 1-13, article id 583Article in journal (Refereed)
    Abstract [en]

    Background: The population growth rate is an important characteristic of any cell culture. During sustained experiments, the growth rate may vary due to competition or adaptation. For instance, in presence of a toxin or a drug, an increasing growth rate indicates that the cells adapt and become resistant. Consequently, time-dependent growth rates are fundamental to follow on the adaptation of cells to a changing evolutionary landscape. However, as there are no tools to calculate the time-dependent growth rate directly by cell counting, it is common to use only end point measurements of growth rather than tracking the growth rate continuously. Results: We present a computer program for inferring the growth rate over time in suspension cells using nothing but cell counts, which can be measured non-destructively. The program was tested on simulated and experimental data. Changes were observed in the initial and absolute growth rates, betraying resistance and adaptation. Conclusions: For experiments where adaptation is expected to occur over a longer time, our method provides a means of tracking growth rates using data that is normally collected anyhow for monitoring purposes. The program and its documentation are freely available at under the permissive zlib license.

  • 22.
    Davila-Rodriguez, Maria Jose
    et al.
    Univ Fed Sao Carlos, Brazil.
    Freire, Thales Souza
    Univ Fed Sao Carlos, Brazil.
    Lindahl, Erik
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Caracelli, Ignez
    Univ Fed Sao Carlos, Brazil.
    Zukerman-Schpector, Julio
    Univ Fed Sao Carlos, Brazil.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Is breaking of a hydrogen bond enough to lead to drug resistance?2020In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 56, no 49, p. 6727-6730Article in journal (Refereed)
    Abstract [en]

    Drug resistance is a serious problem in cancer, viral, bacterial, fungal and parasitic diseases. Examination of crystal structures of protein-drug complexes is often not enough to explain why a certain mutation leads to drug resistance. As an example, the crystal structure of the kinase inhibitor dasatinib bound to the Abl1 kinase shows a hydrogen bond between the drug and residue Thr(315)and very few contacts between the drug and residues Val(299)and Phe(317), yet mutations in those residues lead to drug resistance. In the first case, it is tempting to suggest that the loss of a hydrogen bond leads to drug resistance, whereas in the other two cases it is not known why mutations lead to drug resistance in the first place. We carried out extensive molecular dynamics (MD) simulations and free energy calculations to explain drug resistance to dasatinib from a molecular point of view and show that resistance is due to a multitude of subtle effects. Importantly, our calculations could reproduce the experimental values for the binding energies upon mutations in all three cases and shed light on their origin.

  • 23.
    Todde, Guido
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Pattern and Dynamics of FLT3 Duplications2020In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 60, no 8, p. 4005-4020Article in journal (Refereed)
    Abstract [en]

    FMS-like tyrosine kinase 3 (FLT3) is mutated in similar to 30% of patients that suffer from acute myeloid leukemia (AML). In about 25% of all AML patients, in-frame insertions are observed in the sequence. Most of those insertions are internal tandem duplications (ITDs) of a sequence from the protein. The characteristics of such mutations in terms of length, sequence, and location were hitherto studied in different populations, but not in a comprehensive mutation database. Here, in-frame insertions into the FLT3 gene were extracted from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. These were analyzed with respect to the length, location, and sequence of the mutations. Furthermore, characteristic strings (sequences) of different lengths were identified. Mutations were shown to occur most often in the juxtamembrane zipper (JM-Z) domain of FLT3, followed by the hinge domain and first tyrosine kinase domain (TKD1), upstream of the phosphate-binding loop (P-loop). Interestingly, there are specific hot spot residues where insertions are more likely to occur. The insertions vary in length between one and 67 amino acids, with the largest insertions spanning the phosphate binding loop. Insertions that occur downstream of the P-loop are shorter. Our analysis further shows that acidic and aromatic residues are enriched in the insertions. Finally, molecular dynamics simulations were run for FLT3 with ITD insertions in the hinge and tyrosine kinase domains. On the basis of the findings, a mechanism is proposed for activation by ITDs, according to which there is no direct coupling between the length of the insertion and the activity of the mutated protein. The effect of insertions on the sensitivity of FLT3 to kinase inhibitors is discussed based on our findings.

  • 24.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Università della Svizzera italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Herold, Malte
    University of Luxembourg, Luxembourg.
    Christel, Stephan
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    El Hajjami, Mohamed
    QNLM, China.
    Delogu, Francesco
    Norwegian University of Life Sciences, Norway.
    Ilie, Olga
    Università della Svizzera italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Bellenberg, Sören
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Wilmes, Paul
    University of Luxembourg, Luxembourg.
    Poetsch, Ansgar
    Ruhr University Bochum, Germany;QNLM, China;Ocean University of China, China.
    Sand, Wolfgang
    University Duisburg-Essen, Germany;Donghua University, China;Mining Academy and Technical University Freiberg, Germany.
    Vera, Mario
    Pontificia Universidad Católica de Chile, Chile.
    Pivkin, Igor V.
    Università della Svizzera italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Water.
    Dopson, Mark
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Reverse engineering directed gene regulatory networks from transcriptomics and proteomics data of biomining bacterial communities with approximate Bayesian computation and steady-state signalling simulations2020In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 21, no 1, p. 1-15, article id 23Article in journal (Refereed)
    Abstract [en]

    Background: Network inference is an important aim of systems biology. It enables the transformation of OMICs datasets into biological knowledge. It consists of reverse engineering gene regulatory networks from OMICs data, such as RNAseq or mass spectrometry-based proteomics data, through computational methods. This approach allows to identify signalling pathways involved in specific biological functions. The ability to infer causality in gene regulatory networks, in addition to correlation, is crucial for several modelling approaches and allows targeted control in biotechnology applications. Methods: We performed simulations according to the approximate Bayesian computation method, where the core model consisted of a steady-state simulation algorithm used to study gene regulatory networks in systems for which a limited level of details is available. The simulations outcome was compared to experimentally measured transcriptomics and proteomics data through approximate Bayesian computation. Results: The structure of small gene regulatory networks responsible for the regulation of biological functions involved in biomining were inferred from multi OMICs data of mixed bacterial cultures. Several causal inter- and intraspecies interactions were inferred between genes coding for proteins involved in the biomining process, such as heavy metal transport, DNA damage, replication and repair, and membrane biogenesis. The method also provided indications for the role of several uncharacterized proteins by the inferred connection in their network context. Conclusions: The combination of fast algorithms with high-performance computing allowed the simulation of a multitude of gene regulatory networks and their comparison to experimentally measured OMICs data through approximate Bayesian computation, enabling the probabilistic inference of causality in gene regulatory networks of a multispecies bacterial system involved in biomining without need of single-cell or multiple perturbation experiments. This information can be used to influence biological functions and control specific processes in biotechnology applications.

  • 25.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bjelic, Sinisa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Simulations Studies of Protein Kinases that are Molecular Targets in Cancer2020In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 60, no 7, p. 667-680Article, review/survey (Refereed)
    Abstract [en]

    Protein kinases are enzymes with partially overlapping specificities, many of which are important clinical targets. In this article, we give some background on protein kinases and discuss in more depth four such enzymes that have been studied in our labs using computer simulations. The combination of molecular dynamics simulations and enzyme or cell growth experiments was instrumental to explain why certain mutations lead (or do not lead) to resistance to targeted therapy aimed at these proteins. Stochastic network simulations were used to study protein-protein interactions and suggest points for intervention against tumour growth.

  • 26.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The effects of combination treatments on drug resistance in chronic myeloid leukaemia: an evaluation of the tyrosine kinase inhibitors axitinib and asciminib2020In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 20, no 1, article id 397Article in journal (Refereed)
    Abstract [en]

    Background: Chronic myeloid leukaemia is in principle a treatable malignancy but drug resistance is lowering survival. Recent drug discoveries have opened up new options for drug combinations, which is a concept used in other areas for preventing drug resistance. Two of these are (I) Axitinib, which inhibits the T315I mutation of BCR-ABL1, a main source of drug resistance, and (II) Asciminib, which has been developed as an allosteric BCR-ABL1 inhibitor, targeting an entirely different binding site, and as such does not compete for binding with other drugs. These drugs offer new treatment options. Methods: We measured the proliferation of KCL-22 cells exposed to imatinib–dasatinib, imatinib–asciminib and dasatinib–asciminib combinations and calculated combination index graphs for each case. Moreover, using the median–effect equation we calculated how much axitinib can reduce the growth advantage of T315I mutant clones in combination with available drugs. In addition, we calculated how much the total drug burden could be reduced by combinations using asciminib and other drugs, and evaluated which mutations such combinations might be sensitive to. Results: Asciminib had synergistic interactions with imatinib or dasatinib in KCL-22 cells at high degrees of inhibition. Interestingly, some antagonism between asciminib and the other drugs was present at lower degrees on inhibition. Simulations revealed that asciminib may allow for dose reductions, and its complementary resistance profile could reduce the risk of mutation based resistance. Axitinib, however, had only a minor effect on T315I growth advantage. Conclusions: Given how asciminib combinations were synergistic in vitro, our modelling suggests that drug combinations involving asciminib should allow for lower total drug doses, and may result in a reduced spectrum of observed resistance mutations. On the other hand, a combination involving axitinib was not shown to be useful in countering drug resistance.

  • 27.
    Todde, Guido
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Activation and Inactivation of the FLT3 Kinase: Pathway Intermediates and the Free Energy of Transition2019In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 123, no 26, p. 5385-5394Article in journal (Refereed)
    Abstract [en]

    The aberrant expression of kinases is often associated with pathologies such as cancer and autoimmune diseases. Like other types of enzymes, kinases can adopt active and inactive states, where a shift toward more stable active state often leads to disease. Dozens of kinase inhibitors are, therefore, used as drugs. Most of these bind to either the inactive or active state. In this work, we study the transitions between these two states in FLT3, an important drug target in leukemias. Kinases are composed of two lobes (N- and C-terminal lobes) with the catalytic site in-between. Through projection of the largest motions obtained through molecular dynamics (MD) simulations, we show that each of the end-states (active or inactive) already possess the ability for transition as the two lobes rotate which initiates the transition. A targeted simulation approach known as essential dynamics sampling (EDS) was used to speed up the transition between the two protein states. Coupling the EDS to implicit-solvent MD was performed to estimate the free energy barriers of the transitions. The activation energies were found in good agreement with previous estimates obtained for other kinases. Finally, we identified FLT3 intermediates that assumed configurations that resemble that of the c-Src nonreceptor tyrosine kinase. The intermediates show better binding to the drug ponatinib than c-Src and the inactive state of FLT3. This suggests that targeting intermediate states can be used to explain the drug-binding patterns of kinases and for rational drug design.

  • 28.
    Gagner, Viktor Ahlberg
    et al.
    University of Gothenburg, Sweden.
    Lundholm, Ida
    University of Gothenburg, Sweden.
    Garcia-Bonete, Maria-Jose
    University of Gothenburg, Sweden.
    Rodilla, Helena
    Chalmers University of Technology, Sweden.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Zhaunerchyk, Vitali
    University of Gothenburg, Sweden.
    Bourenkov, Gleb
    DESY, Germany.
    Schneider, Thomas
    DESY, Germany.
    Stake, Jan
    Chalmers University of Technology, Sweden.
    Katona, Gergely
    University of Gothenburg, Sweden.
    Clustering of atomic displacement parameters in bovine trypsin reveals a distributed lattice of atoms with shared chemical properties2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, p. 1-14, article id 19281Article in journal (Refereed)
    Abstract [en]

    Low-frequency vibrations are crucial for protein structure and function, but only a few experimental techniques can shine light on them. The main challenge when addressing protein dynamics in the terahertz domain is the ubiquitous water that exhibit strong absorption. In this paper, we observe the protein atoms directly using X-ray crystallography in bovine trypsin at 100 K while irradiating the crystals with 0.5THz radiation alternating on and off states. We observed that the anisotropy of atomic displacements increased upon terahertz irradiation. Atomic displacement similarities developed between chemically related atoms and between atoms of the catalytic machinery. This pattern likely arises from delocalized polar vibrational modes rather than delocalized elastic deformations or rigid-body displacements. The displacement correlation between these atoms were detected by a hierarchical clustering method, which can assist the analysis of other ultra-high resolution crystal structures. These experimental and analytical tools provide a detailed description of protein dynamics to complement the structural information from static diffraction experiments.

  • 29.
    Todde, Guido
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Conformational modifications induced by internal tandem duplications on the FLT3 kinase and juxtamembrane domains2019In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 21, no 34, p. 18467-18476Article in journal (Refereed)
    Abstract [en]

    he aberrant expression of FLT3 tyrosine kinase is associated primarily with acute myeloid leukaemia. This blood malignancy is often related to the onset of internal tandem duplications (ITDs) in the native sequence of the protein. The ITDs occur mainly in the juxtamembrane domain of the protein and alter the normal activity of the enzyme. In this work, we have studied the native form of FLT3 and six mutants by molecular dynamics simulations. The catalytic activity of FLT3 is exerted by the tyrosine kinase domain (KD) and regulated by the juxtamembrane (JM) domain. Analysis of the dynamics of these two domains have shown that the introduction of ITDs in the JM domain alters both structural and dynamic parameters. The presence of ITDs allowed the protein to span a larger portion of the conformational space, particularly in the JM domain and the activation loop. The FLT3 mutants were found to adopt more stable configurations than the native enzyme. This was due to the different arrangements assumed by the JM domain. Larger fluctuations of the activation loop were found in four of the six mutants. In the native FLT3, the key residue Tyr(572) is involved in a strong and stable interaction with an ion pair. This interaction, which is thought to keep the JM in place hence regulating the activity of the enzyme, was found to break in all FLT3 mutants.

  • 30.
    Georgoulia, Panagiota S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Glykos, Nicholas M.
    University of Thrace, Greece.
    Molecular simulation of peptides coming of age: accurate prediction of folding, dynamics and structures2019In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 664, no March, p. 76-88Article in journal (Refereed)
    Abstract [en]

    The application of molecular dynamics simulations to study the folding and dynamics of peptides has attracted a lot of interest in the last couple of decades. Following the successful prediction of the folding of several proteins using molecular simulation, foldable peptides emerged as a favourable system mainly due to their application in improving protein structure prediction methods and in drug design studies. However, their performance is inherently linked to the accuracy of the empirical force fields used in the simulations, whose optimisation and validation is of paramount importance. Here we review the most important findings in the field of molecular peptide simulations and highlight the significant advancements made over the last twenty years. Special reference is made on the simulation of disordered peptides and the remaining challenge to find a force field able to describe accurately their conformational landscape.

  • 31.
    Steinz, Maarten M.
    et al.
    Karolinska Institutet, Sweden.
    Persson, Malin
    McGill University, Canada.
    Aresh, Bejan
    Stockholm University, Sweden.
    Olsson, Karl
    Karolinska Institutet, Sweden.
    Cheng, Arthur J.
    Karolinska Institutet, Sweden.
    Ahlstrand, Emma
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lilja, Mats
    Karolinska Institutet, Sweden.
    Lundberg, Tommy R.
    Karolinska Institutet, Sweden.
    Rullman, Eric
    Karolinska Institutet, Sweden.
    Ängeby Möller, Kristina
    Karolinska Institutet, Sweden.
    Sandor, Katalin
    Karolinska Institutet, Sweden.
    Ajeganova, Sofia
    Karolinska Institutet, Sweden.
    Yamada, Takashi
    Sapporo Medical University, Japan.
    Beard, Nicole
    University of Canberra, Australia.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Tavi, Pasi
    Karolinska Institutet, Sweden;University of Eastern Finland, Finland.
    Kenne, Ellinor
    Karolinska Institutet, Sweden.
    Svensson, Camilla I.
    Karolinska Institutet, Sweden.
    Rassier, Dilson E.
    McGill University, Canada.
    Karlsson, Roger
    Stockholm University, Sweden.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Gustafsson, Thomas
    Karolinska Institutet, Sweden.
    Lanner, Johanna T.
    Karolinska Institutet, Sweden.
    Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis2019In: JCI Insight, ISSN 2324-7703, Vol. 4, no 9, p. 1-16, article id e126347Article in journal (Refereed)
    Abstract [en]

    Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here we show that oxidative post-translational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde adduct (MDA) modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located to three distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritis mice and RA patients. Moreover, molecular dynamic simulations revealed that these areas, here coined “hotspots”, are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and provide novel leads for targeted therapeutic treatment to improve muscle function.

  • 32.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Simulations of Biomolecules in Electrolyte Solutions2019In: Advanced Theory and Simulations, E-ISSN 2513-0390, Vol. 2, no 4, p. 1-10, article id 1800163Article in journal (Refereed)
    Abstract [en]

    Biomolecules including proteins, lipid membranes, and nucleic acids operate at an aqueous milieu that includes solvated ions. The interactions with ions affect biomolecules in different ways depending on the nature of the solute and the type of the ions. The dynamic nature of small soluble ions makes it difficult to follow them by structural methods. Consequently, theories were developed to explain how biomolecules interact in an environment that includes electrolytes. Moreover, simulations studies are often used to study such systems at the molecular or atomistic level. The status of the field, and inparticular of simulation studies, is the subject of this progress report.

  • 33.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Specific Ion and Concentration Effects in Acetate Solutions with Na+, K+ and Cs+2019In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 20, no 8, p. 1006-1010Article in journal (Refereed)
    Abstract [en]

    How salt ions affect solutes and the water beyond the solvation shell is not well understood. Molecular dynamics simulations of alkali-acetate solutions were analysed here in order to examine if, and how, different cations and solute concentrations affect the water structure and the interactions between water and acetates. The results revealed that water structure is perturbed to more than 1 nm away from the acetates and that this effect is more pronounced in physiological than in molar electrolyte concentrations. Analysis of simulations of a soluble protein revealed that the water orientation is perturbed to at least 1.5 nm from the protein structure. Furthermore, modifications to the orientation of water around carboxylate side chains were shown to depend on the local environment on the protein surface, and could extend to well over 1 nm, which may have an effect on protein dynamics during MD simulations in small water boxes.

  • 34.
    Lindström, Jonathan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    de Wijn, Astrid S.
    Norwegian University of Science and Technology, Norway.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Stochastic modelling of tyrosine kinase inhibitor rotation therapy in chronic myeloid leukaemia2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, p. 1-13, article id 508Article in journal (Refereed)
    Abstract [en]

    BackgroundResistance towards targeted cancer treatments caused by single nucleotide variations is a major issue in many malignancies. Currently, there are a number of available drugs for chronic myeloid leukaemia (CML), which are overcome by different sets of mutations. The main aim of this study was to explore if it can be possible to exploit this and create a treatment protocol that outperforms each drug on its own.MethodsWe present a computer program to test different treatment protocols against CML, based on available resistance mutation growth data. The evolution of a relatively stable pool of cancer stem cells is modelled as a stochastic process, with the growth of cells expressing a tumourigenic protein (here, Abl1) and any emerging mutants determined principally by the drugs used in the therapy.ResultsThere can be some benefit to Bosutinib-Ponatinib rotation therapy even if the mutation status is unknown, whereas Imatinib-Nilotinib rotation is unlikely to improve the outcomes. Furthermore, an interplay between growth inhibition and selection effects generates a non-linear relationship between drug doses and the risk of developing resistance.ConclusionsDrug rotation therapy might be able to delay the onset of resistance in CML patients without costly ongoing observation of mutation status. Moreover, the simulations give credence to the suggestion that lower drug concentrations may achieve better results following major molecular response in CML.

  • 35.
    Georgoulia, Panagiota S.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Todde, Guido
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Bjelic, Sinisa
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia2019In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1863, no 4, p. 732-741Article in journal (Refereed)
    Abstract [en]

    Background

    Abl1 is a protein tyrosine kinase whose aberrant activation due to mutations is the culprit of several cancers, most notably chronic myeloid leukaemia. Several Abl1 inhibitors are used as anti-cancer drugs. Unfortunately, drug resistance limits their effectiveness. The main cause for drug resistance is mutations in the kinase domain (KD) of Abl1 that evolve in patients. The T315I mutation confers resistance against all clinically-available inhibitors except ponatinib. Resistance to ponatinib can develop by compound (double) mutations.

    Methods

    Kinetic measurements of the KD of Abl1 and its mutants were carried out to examine their catalytic activity. Specifically, mutants that lead to drug resistance against ponatinib were considered. Molecular dynamics simulations and multiple sequence analysis were used for explanation of the experimental findings.

    Results

    The catalytic efficiency of the T315I pan-resistance mutant is more than two times lower than that of the native KD. All ponatinib resistant mutations restore the catalytic efficiency of the enzyme. Two of them (G250E/T315I and Y253H/E255V) have a catalytic efficiency that is more than five times that of the native KD.

    Conclusions

    The measurements and analysis suggest that resistance is at least partially due to the development of a highly efficient kinase through subsequent mutations. The simulations highlight modifications in two structurally important regions of Abl1, the activation and phosphate binding loops, upon mutations.

    General significance

    Experimental and computational methods were used together to explain how mutations in the kinase domain of Abl1 lead to resistance against the most advanced drug currently in use to treat chronic myeloid leukaemia.

  • 36.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland.
    Jensen, Rebecca
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, no 1, p. 1-8, article id 569Article in journal (Refereed)
    Abstract [en]

    Background: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. Methods: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors. Results: The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and P13K appeared as a significant factor in controlling tumour proliferation. Conclusions: Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

  • 37.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Buetti-Dinh, Antoine
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Universita’ della Svizzera Italiana, Switzerland;Swiss Institute of Bioinformatics, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    An interactive computer lab of the galvanic cell for students in biochemistry2018In: Biochemistry and molecular biology education, ISSN 1470-8175, E-ISSN 1539-3429, Vol. 46, no 1, p. 58-65Article in journal (Refereed)
    Abstract [en]

    We describe an interactive module that can be used to teach basic concepts in electrochemistry and thermodynamics to first year natural science students. The module is used together with an experimental laboratory and improves the students’ understanding of thermodynamic quantities such as ΔrG, ΔrH, and ΔrS that are calculated but not directly measured in the lab. We also discuss how new technologies can substitute some parts of experimental chemistry courses, and improve accessibility to course material. Cloud computing platforms such as CoCalc facilitate the distribution of computer codes and allow students to access and apply interactive course tools beyond the course's scope. Despite some limitations imposed by cloud computing, the students appreciated the approach and the enhanced opportunities to discuss study questions with their classmates and instructor as facilitated by the interactive tools. 

    Download full text (pdf)
    fulltext accepted manuscript
  • 38.
    Buetti-Dinh, Antoine
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Università della Svizzera Italiana, Italy;Swiss Institute of Bioinformatics, Switzerland.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK62018In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 19, p. 1-13, article id 155Article in journal (Refereed)
    Abstract [en]

    Background

    Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies.

    Results

    Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone.

    Conclusions

    The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.

  • 39.
    Steinz, Maarten
    et al.
    Karolinska Institutet, Sweden.
    Malin, Persson
    Karolinska Institutet, Sweden.
    Bejan, Aresh
    Stockholm University, Sweden.
    Cheng, Arthur
    Karolinska Institutet, Sweden.
    Ahlstrand, Emma
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ajeganova, Sofia
    Karolinska Institutet, Sweden.
    Rassier, Dilson
    McGill Univ, Canada.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Roger
    Stockholm University, Sweden.
    Gustafsson, Thomas
    Karolinska Institutet, Sweden.
    Lanner, Johanna
    Karolinska Institutet, Sweden.
    Identification of oxidative hotspots on actin which promote skeletal muscle weakness in rheumatoid arthritis2018In: Free Radical Biology and Medicine, 2018, Vol. 128: Supplement 1, p. S106-, article id 247Conference paper (Refereed)
  • 40.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Membrane-Ion Interactions2018In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 3, p. 453-460Article in journal (Refereed)
    Abstract [en]

    Biomembranes assemble and operate at the interface with electrolyte solutions. Interactions between ions in solutions and the lipid affect the membrane structure, dynamics and electrostatic potential. In this article, I review some of the experimental and computational methods that are used to study membrane-ions interactions. Experimental methods that account for membrane-ion interactions directly and indirectly are presented first. Then, studies in which molecular dynamics simulations were used to gain an understanding of membrane-ion interactions are surveyed. Finally, the current view on membrane-ion interactions and their significance is briefly discussed.

  • 41.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Khalid, Syma
    Univ Southampton, UK.
    Aponte-Santamaria, Camilo
    Univ Los Andes, Colombia;Heidelberg Univ, Germany.
    Arutyunova, Elena
    Univ Alberta, Canada.
    Becker, Marlon
    Univ Munster, Germany.
    Boyd, Kevin J.
    Univ Connecticut, USA.
    Christensen, Mikkel
    Aarhus Univ, Denmark;Sinodanish Ctr Educ & Res, China.
    Coimbra, Joao T. S.
    Univ Porto, Portugal.
    Concilio, Simona
    Univ Salerno, Italy.
    Daday, Csaba
    Heidelberg Inst Theoret Studies, Germany.
    van Eerden, Floris J.
    Univ Groningen, Netherlands.
    Fernandes, Pedro A.
    Univ Porto, Portugal.
    Graeter, Frauke
    Heidelberg Univ, Germany;Heidelberg Inst Theoret Studies, Germany.
    Hakobyan, Davit
    Univ Munster, Germany.
    Heuer, Andreas
    Univ Munster, Germany.
    Karathanou, Konstantina
    Free Univ Berlin, Germany.
    Keller, Fabian
    Univ Munster, Germany.
    Lemieux, M. Joanne
    Univ Alberta, Canada.
    Marrink, Siewert J.
    Univ Groningen, Netherlands.
    May, Eric R.
    Univ Connecticut, USA.
    Mazumdar, Antara
    Univ Groningen, Netherlands.
    Naftalin, Richard
    Kings Coll London, UK.
    Pickholz, Monica
    Univ Buenos Aires, Argentina.
    Piotto, Stefano
    Univ Salerno, Italy.
    Pohl, Peter
    Johannes Kepler Univ Linz, Austria.
    Quinn, Peter
    Kings Coll London, UK.
    Ramos, Maria J.
    Univ Porto, Portugal.
    Schiott, Birgit
    Aarhus Univ, Denmark.
    Sengupta, Durba
    Natl Chem Lab, India.
    Sessa, Lucia
    Univ Salerno, Italy.
    Vanni, Stefano
    Univ Fribourg, Switzerland.
    Zeppelin, Talia
    Aarhus Univ, Denmark.
    Zoni, Valeria
    Univ Fribourg, Switzerland.
    Bondar, Ana-Nicoleta
    Free Univ Berlin, Germany.
    Domene, Carmen
    Univ Bath, UK;Univ Oxford, UK.
    Understanding Conformational Dynamics of Complex Lipid Mixtures Relevant to Biology2018In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 5-6, p. 609-631Article, review/survey (Refereed)
    Abstract [en]

    This is a perspective article entitled "Frontiers in computational biophysics: understanding conformational dynamics of complex lipid mixtures relevant to biology" which is following a CECAM meeting with the same name.

  • 42.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Agmon, Noam
    Hebrew Univ Jerusalem, Israel.
    Charge Transfer in Proteins: In Celebration of Hemi Gutman's 80th Birthday2017In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 5, p. 355-356Article in journal (Other academic)
  • 43.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Zukerman Schpector, Julio
    Universidade Federal de São Carlos, Brazil.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Computer simulations of alkali-acetate solutions: Accuracy of the forcefields in difference concentrations2017In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 147, p. 1-10, article id 194102Article in journal (Refereed)
    Abstract [en]

    When proteins are solvated in electrolyte solutions that contain alkali ions, the ions interact mostlywith carboxylates on the protein surface. Correctly accounting for alkali-carboxylate interactionsis thus important for realistic simulations of proteins. Acetates are the simplest carboxylates thatare amphipathic, and experimental data for alkali acetate solutions are available and can be comparedwith observables obtained from simulations. We carried out molecular dynamics simulations of alkali acetate solutions using polarizable and non-polarizable forcefields and examined the ionacetateinteractions. In particular, activity coefficients and association constants were studied in a range of concentrations (0.03, 0.1, and 1M). In addition, quantum-mechanics (QM) based energy decomposition analysis was performed in order to estimate the contribution of polarization, electrostatics, dispersion, and QM (non-classical) effects on the cation-acetate and cation-water interactions. Simulations of Li-acetate solutions in general overestimated the binding of Li+ and acetates. In lower concentrations, the activity coefficients of alkali-acetate solutions were too high, which is suggested to be due to the simulation protocol and not the forcefields. Energy decomposition analysis suggested that improvement of the forcefield parameters to enable accurate simulations of Li-acetate solution scan be achieved but may require the use of a polarizable forcefield. Importantly, simulations with some ion parameters could not reproduce the correct ion-oxygen distances, which calls for caution in thechoice of ion parameters when protein simulations are performed in electrolyte solutions.

    Download full text (pdf)
    Accepted_Manuscript
  • 44.
    Karlsson, Björn C. G.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Dilution of whisky - the molecular perspective2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, no 6489Article in journal (Refereed)
    Abstract [en]

    Whisky is distilled to around 70% alcohol by volume (vol-%) then diluted to about 40 vol-%, and often drunk after further slight dilution to enhance its taste. The taste of whisky is primarily associated with amphipathic molecules, such as guaiacol, but why and how dilution enhances the taste is not well understood. We carried out computer simulations of water-ethanol mixtures in the presence of guaiacol, providing atomistic details on the structure of the liquid mixture. We found that guaiacol is preferentially associated with ethanol, and, therefore, primarily found at the liquid-air interface in mixtures that contain up to 45 vol-% of ethanol. At ethanol concentrations of 59 vol-% or higher, guaiacol is increasingly surrounded by ethanol molecules and is driven to the bulk. This indicates that the taste of guaiacol in the whisky would be enhanced upon dilution prior to bottling. Our findings may apply to other flavour-giving amphipathic molecules and could contribute to optimising the production of spirits for desired tastes. Furthermore, it sheds light on the molecular structure of water-alcohol mixtures that contain small solutes, and reveals that interactions with the water may be negligible already at 89 vol-% of ethanol.

    Download full text (pdf)
    fulltext
  • 45.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Hermansson, Kersti
    Uppsala University.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Interaction Energies in Complexes of Zn and Amino Acids: A Comparison of Ab Initio and Force Field Based Calculations2017In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 121, no 13, p. 2643-2654Article in journal (Refereed)
    Abstract [en]

    Zinc plays important roles in structural stabilization of proteins, eniyine catalysis, and signal transduction. Many Zn binding sites are located at the interface between the protein and the cellular fluid. In aqueous solutions, Zn ions adopt an octahedral coordination, while in proteins zinc can have different coordinations, with a tetrahedral conformation found most frequently. The dynainics of Zn binding to proteins and the formation of complexes that involve Zn are dictated by interactions between Zn and its binding partners. We calculated the interaction energies between Zn and its ligands in complexes that mimic protein binding sites and in Zn complexes of water and one or two amino acid moieties, using quantum mechanics (QM) and molecular mechanics (MM). It was found that MM calculations that neglect or only approximate polarizability did not reproduce even the relative order of the QM interaction energies in these complexes. Interaction energies calculated with the CHARMM-Diode polarizable force field agreed better with the ab initio results,:although the deviations between QM and MM were still rather large (40-96 kcallmol). In order to gain further insight into Zn ligand interactions, the free energies of interaction were estimated by QM calculations with continuum solvent representation, and we performed energy decomposition analysis calculations to examine the characteristics of the different complexes. The ligand-types were found to have high impact on the relative strength of polarization and electrostatic interactions. Interestingly, ligand ligand interactions did not play a significant role in the binding of Zn. Finally) analysis of ligand exchange energies suggests that carboxylates could be exchanged with water molecules, which explains the flexibility in Zn:binding dynamics. An exchange between earboxylate (Asp/Glii) and imidazole (His) is less likely.

  • 46.
    Maganhi, Stella Hernandez
    et al.
    Federal University of São Carlos, Brazil.
    Jensen, Patrizia
    National Center for Tumor Diseases (NCT), Germany;German Cancer Research Center (DKFZ) Heidelberg, Germany.
    Caracelli, Ignez
    Federal University of São Carlos, Brazil.
    Schpector, Julio Zukerman
    Federal University of São Carlos, Brazil.
    Froehling, Stefan
    National Center for Tumor Diseases (NCT), Germany;German Cancer Research Center (DKFZ) Heidelberg, Germany ; Heidelberg University Hospital, Germany ; German Cancer Consortium (DKTK), Germany.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein2017In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 26, no 4, p. 870-879Article in journal (Refereed)
    Abstract [en]

    Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)-rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilized the drug in its binding site and that were not observed in the crystal structure of the protein-drug complex. These included a hydrogen bond to His 100 that was hitherto not reported and several hydrophobic contacts. Evolutionary-based bioinformatic analysis was used to suggest two mutants, D163G and H100L that would potentially yield drug resistance, as they lead to loss of important protein-drug interactions without hindering the viability of the protein. One of the mutants involved a change in the glycine of the well-conserved DFG motif of the kinase. Interestingly, CDK6-dependent human AML cells stably expressing either mutant retained sensitivity to palbociclib, indicating that the protein-drug interactions are not affected by these. Furthermore, the cells were proliferative in the absence of palbociclib, indicating that the Asp to Gly mutation in the DFG motif did not interfere with the catalytic activity of the protein.

  • 47.
    Becconi, Olga
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Cagliari, Italy.
    Ahlstrand, Emma
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Salis, Andrea
    University of Cagliari, Italy.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Protein-ion Interactions: Simulations of Bovine Serum Albumin in Physiological Solutions of NaCl, KCl and LiCl2017In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 5, p. 403-412Article in journal (Refereed)
    Abstract [en]

    Specific interactions that depend on the nature of electrolytes are observed when proteins and other molecules are studied by potentiometric, spectroscopic and theoretical methods at high salt concentrations. More recently, it became clear that such interactions may also be observed in solutions that can be described by the Debye-Hückel theory, i.e., at physiological (0.1 mol dm−3) and lower concentrations. We carried out molecular dynamics simulations of bovine serum albumin in physiological solutions at T=300 and 350 K. Analysis of the simulations revealed some differences between LiCl solutions and those of NaCl and KCl. The binding of Li+ ions to the protein was associated with a negative free energy of interaction whereas much fewer Na+ and K+ ions were associated with the protein surface. Interestingly, unlike other proteins BSA does not show a preference to Na+ over K+. Quantum chemical calculations identified a significant contribution from polarisation to the hydration of Li+ and (to a lesser degree) Na+, which may indicate that polarisable force-fields will provide more accurate results for such systems.

  • 48.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib2017In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 85, no 11, p. 2143-2152Article in journal (Refereed)
    Abstract [en]

    Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is a drug target for leukemias. Several potent inhibitors of FLT3 exist, and bind to the inactive form of the enzyme. Unfortunately, resistance due to mutations in the kinase domain of FLT3 limits the therapeutic effects of these inhibitors. As in many other cases, it is not straightforward to explain why certain mutations lead to drug resistance. Extensive fully atomistic molecular dynamics (MD) simulations of FLT3 were carried out with an inhibited form (FLT-quizartinib complex), a free (apo) form, and an active conformation. In all cases, both the wild type (wt) proteins and two resistant mutants (D835F and Y842H) were studied. Analysis of the simulations revealed that impairment of protein-drug interactions cannot explain the resistance mutations in question. Rather, it appears that the active state of the mutant forms is perturbed by the mutations. It is therefore likely that perturbation of deactivation of the protein (which is necessary for drug binding) is responsible for the reduced affinity of the drug to the mutants. Importantly, this study suggests that it is possible to explain the source of resistance by mutations in FLT3 by an analysis of unbiased MD simulations.

  • 49.
    Katona, Gergely
    et al.
    University of Gothenburg, Sweden.
    Lundholm, Ida
    University of Gothenburg, Sweden.
    Rodilla, Helena
    Chalmers University of Technology, Sweden.
    Garcia-Bonete, Maria-Jose
    University of Gothenburg, Sweden.
    Duelli, Annette
    University of Gothenburg, Sweden.
    Wahlgren, Weixiao Y
    University of Gothenburg, Sweden.
    Bourenkov, Gleb
    DESY, European Mol Biol Lab Hamburg Outstn, Germany.
    Vukusic, Josip
    Chalmers University of Technology, Sweden.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Schneider, Thomas
    DESY, European Mol Biol Lab Hamburg Outstn, Germany.
    Stake, Jan
    Chalmers University of Technology, Sweden.
    Bayesian analysis of non-thermal structural changes induced by terahertz radiation in protein crystals2016In: 2016 41ST INTERNATIONAL CONFERENCE ON INFRARED, MILLIMETER, AND TERAHERTZ WAVES (IRMMW-THZ), IEEE conference proceedings, 2016Conference paper (Refereed)
    Abstract [en]

    We have periodically (25ms on - 25ms off) illuminated lysozyme crystals with 0.4 THz radiation and simultaneously monitored their X-ray diffraction intensity in order to study non-thermal structural changes in the protein. In this work we analyze the X-ray scaled and unmerged diffraction intensity observations using a multivariate Bayesian model in order to improve the accuracy of the intensity estimates. The diffraction intensity pairs of the illuminated and non-illuminated state show a predominantly positive correlation. The correlation decreases with increasing resolution suggesting that finer slicing and faster sampling of the rocking curve may further improve the accuracy and effect size of structure factor amplitude differences, making the interpretation of structural changes more straightforward. The improved analysis retains the most important structural features described previously (in helix 3) and provide addition details about the B-factor changes close to the substrate binding site.

  • 50.
    Pineda De Castro, Luis Felipe
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Dopson, Mark
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Biological Membranes in Extreme Conditions: Anionic Tetraether Lipid Membranes and Their Interactions with Sodium and Potassium2016In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, no 41, p. 10628-10634Article in journal (Refereed)
    Abstract [en]

    Archaea such as Sulfolobus acidocaldarius tolerate extreme temperatures and high acidity and can grow in the presence of toxic metals and low concentrations of Na+ or K+. It is believed that their unique tetraether membranes protect them from harsh environments and allow their survival under such conditions. We used molecular dynamics simulations to study membranes comprising glycerol dialkylnonitol tetraether lipids, which are the main component of S. acidocaldariusmembranes, in solutions containing different concentrations of NaCl and KCl or with Na+ or K+counterions (trace cations, 0 M). Anionic binding sites on the membranes were almost 50% occupied in the presence of counterions. The free energy of cation–phosphate complexation and the residence times of ions near the membranes were found to be both ion- and concentration-dependent. Sodium ions had more favorable interactions with the membranes and a longer residence time, whereas higher cation concentrations led to shorter ion residence times. When only counterions were present in the solutions, large residence times suggested that the membrane may function as a cation-attracting reservoir. The results suggested that the ions can be easily transferred to the cytoplasm as needed, explaining the growth curves of S. acidocaldarius under different salinities and pH.

    Download full text (pdf)
    Accepted_Version
12 1 - 50 of 97
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf