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  • 1.
    Golker, Kerstin
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    A Functional Monomer Is Not Enough: Principal Component Analysis of the Influence of Template Complexation in Pre-Polymerization Mixtures on Imprinted Polymer Recognition and Morphology2014In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 15, no 11, p. 20572-20584Article in journal (Refereed)
    Abstract [en]

    In this report, principal component analysis (PCA) has been used to explore the influence of template complexation in the pre-polymerization phase on template molecularly imprinted polymer (MIP) recognition and polymer morphology. A series of 16 bupivacaine MIPs were studied. The ethylene glycol dimethacrylate (EGDMA)-crosslinked polymers had either methacrylic acid (MAA) or methyl methacrylate (MMA) as the functional monomer, and the stoichiometry between template, functional monomer and crosslinker was varied. The polymers were characterized using radioligand equilibrium binding experiments, gas sorption measurements, swelling studies and data extracted from molecular dynamics (MD) simulations of all-component pre-polymerization mixtures. The molar fraction of the functional monomer in the MAA-polymers contributed to describing both the binding, surface area and pore volume. Interestingly, weak positive correlations between the swelling behavior and the rebinding characteristics of the MAA-MIPs were exposed. Polymers prepared with MMA as a functional monomer and a polymer prepared with only EGDMA were found to share the same characteristics, such as poor rebinding capacities, as well as similar surface area and pore volume, independent of the molar fraction MMA used in synthesis. The use of PCA for interpreting relationships between MD-derived descriptions of events in the pre-polymerization mixture, recognition properties and morphologies of the corresponding polymers illustrates the potential of PCA as a tool for better understanding these complex materials and for their rational design.

  • 2.
    Zabriskie, Matthew S.
    et al.
    University of Utah, USA.
    Eide, Christopher A.
    Oregon Health & Science University, USA;Howard Hughes Medical Institute, USA.
    Tantravahi, Srinivas K.
    University of Utah, USA.
    Vellore, Nadeem A.
    University of Utah, USA.
    Estrada, Johanna
    University of Utah, USA.
    Nicolini, Franck E.
    Centre Hospitalier Lyon Sud, France.
    Khoury, Hanna J.
    Emory University, USA.
    Larson, Richard A.
    University of Chicago, USA.
    Konopleva, Marina
    University of Texas, USA.
    Cortes, Jorge E.
    University of Texas, USA.
    Kantarjian, Hagop
    University of Texas, USA.
    Jabbour, Elias J.
    University of Texas, USA.
    Kornblau, Steven M.
    University of Texas, USA.
    Lipton, Jeffrey H.
    University of Toronto, Canada.
    Rea, Delphine
    Hospital Saint-Louis, France.
    Stenke, Leif
    Karolinska Institutet.
    Barbany, Gisela
    Karolinska Institutet.
    Lange, Thoralf
    University of Leipzig, Germany.
    Hernandez-Boluda, Juan-Carlos
    Hospital Clı´nico Universitario, Spain.
    Ossenkoppele, Gert J.
    VU University Medical Center, Netherlands.
    Press, Richard D.
    Oregon Health & Science University, USA.
    Chuah, Charles
    Singapore General Hospital, Singapore.
    Goldberg, Stuart L.
    John Theurer Cancer Center at Hackensack University Medical Center, USA.
    Wetzler, Meir
    Roswell Park Cancer Institute, USA.
    Mahon, Francois-Xavier
    Centre Hospitalier Universitaire de Bordeaux, France.
    Etienne, Gabriel
    Institut Bergonie, France.
    Baccarani, Michele
    University of Bologna, Italy.
    Soverini, Simona
    University of Bologna, Italy.
    Rosti, Gianantonio
    University of Bologna, Italy.
    Rousselot, Philippe
    Université de Versailles, France.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Deininger, Marie
    University of Utah, USA.
    Reynolds, Kimberly R.
    University of Utah, USA.
    Heaton, William L.
    University of Utah, USA.
    Eiring, Anna M.
    University of Utah, USA.
    Pomicter, Anthony D.
    University of Utah, USA.
    Khorashad, Jamshid S.
    University of Utah, USA.
    Kelley, Todd W.
    University of Utah, USA.
    Baron, Riccardo
    University of Utah, USA.
    Druker, Brian J.
    Oregon Health & Science University Knight Cancer Institute, USA;Howard Hughes Medical Institute, USA.
    Deininger, Michael W.
    University of Utah, USA.
    O'Hare, Thomas
    University of Utah, USA.
    BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia2014In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 26, no 3, p. 428-442Article in journal (Refereed)
    Abstract [en]

    Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.

  • 3.
    Nicholls, Ian A.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Bioorganic & Biophysical Chemistry Laboratory.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Andersson, Per-Ola
    Swedish Defence Research Agency Umeå, Sweden.
    Method and apparatus for detecting pharmaceuticals in a sample2014Patent (Other (popular science, discussion, etc.))
  • 4.
    Cleland, Dougal
    et al.
    The University of Newcastle, Australia.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    McCluskey, Adam
    The University of Newcastle, Australia.
    Molecular dynamics approaches to the design and synthesis of PCB targeting molecularly imprinted polymers: interference to monomer-template interactions in imprinting of 1,2,3-trichlorobenzene2014In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, no 5, p. 844-853Article in journal (Refereed)
    Abstract [en]

    The interactions between each component of the pre-polymerisation mixtures used in the synthesis of molecularly imprinted polymers (MIP) specific for 1,2,3,4,5-pentachlorobenzene (1) and 1,2,3-trichlorobenzene (2) were examined in four molecular dynamics simulations. These simulations revealed that the relative frequency of functional monomer template (FM T) interactions was consistent with results obtained by the synthesis and evaluation of the actual MIPs. The higher frequency of 1 interaction with tri-methylstyrene (TMS; 54.7%) than 1 interaction with pentafluorostyrene (PFS; 44.7%) correlated with a higher imprinting factor (IF) of 2.1 vs. 1.7 for each functional monomer respectively. The higher frequency of PFS interactions with 2 (29.6%) than TMS interactions with 2 (1.9%) also correlated well with the observed differences in IF (3.7) of 2 MIPs imprinted using PFS as the FM than the IF (2,8) of 2 MIPs imprinted using TMS as the FM. The TMS-1 interaction dominated the molecular simulation due to high interaction energies, but the weaker TMS-2 resulted in low interaction maintenance, and thus lower IF values. Examination of the other pre-polymerisation mixture components revealed that the low levels of TMS-2 interaction was, in part, due to interference caused by the cross linker (CL) ethyleneglycol dimethylacrylate (EGDMA) interactions with TMS. The main reason was, however, attributed to MeOH interactions with TMS in both a hydrogen bond and perpendicular configuration. This positioned a MeOH directly above the it-orbital of all TMS for an average of 63.8% of MD2 creating significant interference to pi-pi stacking interactions between 2 and TMS. These findings are consistent with the deviation from the 'normal' molecularly imprinted polymer synthesis ratio of 1 : 4 : 20 (T : FM : CL) of 20 : 1 : 29 and 15 : 6 : 29 observed with 2 and TMS and PFS respectively. Our molecular dynamics simulations correctly predicted the high level of interference from other MIP synthesis components. The effect on PFS-1 interaction by MeOH was significantly lower and thus this system was not adversely affected.

  • 5.
    Shoravi, Siamak
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    On the Influence of Crosslinker on Template Complexation in Molecularly Imprinted Polymers: A Computational Study of Prepolymerization Mixture Events with Correlations to Template-Polymer Recognition Behavior and NMR Spectroscopic Studies2014In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 15, no 6, p. 10622-10634Article in journal (Refereed)
    Abstract [en]

    Aspects of the molecular-level basis for the function of ethylene glycol dimethacrylate and trimethylolproprane trimethacrylate crosslinked methacrylic acid copolymers molecularly imprinted with (S)-propranolol have been studied using a series of all-component and all-atom molecular dynamics studies of the corresponding prepolymerization systems. The crosslinking agents were observed to contribute to template complexation, and the results were contrasted with previously reported template-recognition behavior of the corresponding polymers. Differences in the extent to which the two crosslinkers interacted with the functional monomer were identified, and correlations were made to polymer-ligand recognition behavior and the results of nuclear magnetic resonance spectroscopic studies studies. This study demonstrates the importance of considering the functional monomer-crosslinker interaction when designing molecularly imprinted polymers, and highlights the often neglected general contribution of crosslinker to determining the nature of molecularly imprinted polymer-template selectivity.

  • 6.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Ctr Biomat Chem.
    Structural and computational insights into the versatility of cadmium binding to proteins2014In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 43, no 7, p. 2878-2887Article in journal (Refereed)
    Abstract [en]

    Cadmium is a highly toxic group XII metal, similar to zinc and mercury. Unlike zinc, which is one of the most common metal cofactors in biology, cadmium is highly toxic. Many Zn2+-binding proteins can bind Cd2+-ions without significantly affecting their structures. Here, the protein data bank is analysed with regard to protein-cadmium interactions, which shows that cadmium can bind to a variety of ion binding sites in proteins. Statistical analysis of Cd2+-side chain interactions is compared with a similar analysis of other ions. This analysis reveals that with regard to amino acid side-chain preference, Cd2+ is more similar to Mn2+ than to Zn2+ or Hg2+. Finally, the interaction energies of three native metal binding proteins are calculated where Cd2+ binds instead of Zn2+, Ca2+ or Cu2+. The interaction energies are decomposed into individual components whose contributions are discussed.

  • 7.
    Chavan, Swapnil
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Karlsson, Björn C. G.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ballabio, Davide
    University of Milano-Bicocca, Italy.
    Consonni, Viviana
    University of Milano-Bicocca, Italy.
    Todeschini, Roberto
    University of Milano-Bicocca, Italy.
    Towards Global QSAR Model Building for Acute Toxicity: Munro Database Case Study2014In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 15, no 10, p. 18162-18174Article in journal (Refereed)
    Abstract [en]

    A series of 436 Munro database chemicals were studied with respect to their corresponding experimental LD50 values to investigate the possibility of establishing a global QSAR model for acute toxicity. Dragon molecular descriptors were used for the QSAR model development and genetic algorithms were used to select descriptors better correlated with toxicity data. Toxic values were discretized in a qualitative class on the basis of the Globally Harmonized Scheme: the 436 chemicals were divided into 3 classes based on their experimental LD50 values: highly toxic, intermediate toxic and low to non-toxic. The k-nearest neighbor (k-NN) classification method was calibrated on 25 molecular descriptors and gave a non-error rate (NER) equal to 0.66 and 0.57 for internal and external prediction sets, respectively. Even if the classification performances are not optimal, the subsequent analysis of the selected descriptors and their relationship with toxicity levels constitute a step towards the development of a global QSAR model for acute toxicity.

  • 8.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. University of Zürich, Switzerland.
    Caflisch, Amedeo
    University of Zürich, Switzerland.
    Wild type and mutants of the HET-s(218-289) prion show different flexibility at fibrillar ends: A simulation study2014In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 82, no 3, p. 399-404Article in journal (Refereed)
    Abstract [en]

    The C-terminal segment (residues 218–289) of the HET-s protein of the filamentous fungus Podosporina anserina is a prion-forming domain. The structural model of the HET-s(218–289) amyloid fibril based on solid-state nuclear magnetic resonance (NMR) restraints shows a β solenoid topology which is comprised of a β-sheet core and interconnecting loops. For the single-point mutants Phe286Ala and Trp287Ala, slower aggregation rates in vitro and loss of prionic infectivity have been reported recently. Here we have used molecular dynamics to compare the flexibility of the mutants and wild type. The simulations, initiated from a trimeric aggregate extracted from the NMR structural model, show structural stability on a 100-ns time scale for wild type and mutants. Analysis of the fluctuations along the simulations reveals that the mutants are less flexible than the wild type in the C-terminal segment at only one of the two external monomers. Analysis of interaction energy and buried accessible surface indicates that residue Phe286 in particular is stabilized in the Trp287Ala mutant. The simulation results provide an atomistic explanation of the suggestion (based on indirect experimental evidence) that flexibility at the protofibril end(s) is required for fibril elongation. Moreover, they provide further evidence that the growth of the HET-s amyloid fibril is directional.

  • 9.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Drug Resistance Missense Mutations in Cancer Are Subject to Evolutionary Constraints2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 12, article id e82059Article in journal (Refereed)
    Abstract [en]

    Several tumor types are sensitive to deactivation of just one or very few genes that are constantly active in the cancer cells,a phenomenon that is termed oncogene addiction'. Drugs that target the products of those oncogenes can yield a temporary relief, and even complete remission. Unfortunately, many patients receiving oncogene-targeted therapies relapse on treatment. This often happens due to somatic mutations in the oncogene (resistance mutations"). 'Compound mutations', which in the context of cancer drug resistance are defined as two or more mutations of the drug target in the same clone may lead to enhanced resistance against the most selective inhibitors. Here, it is shown that the vast majority the resistance mutations occurring in cancer patients treated with tyrosin kinase inhibitors aimed at three different proteins follow an evolutionary pathway. Using bioinforrnatic analysis tools, found that the drug-resistance mutations in the tyrosine kinase domains of Abl1, ALK and exons 20 and 21 of EGFR favour transformations to residues that can be identified in similar positions in evolutionary related proteins. The results demonstrate that evolutionary pressure shapes the mutational landscape in the case of drug-resistance somatic mutations. The constraints on the mutational landscape suggest that it may be possible to counter single drug-resistance point mutations. The observation of relatively many resistance mutations in Abl1, but not in the other genes, is explained by the fact that mutations in Abl1 tend to be biochemically conservative, whereas mutations in EGFR and ALK tend to be radical. Analysis of Abl1 compound mutations suggests that such mutations are more prevalent than hitherto reported and may be more difficult to counter. This supports the notion that such mutations may provide an escape route for targeted cancer drug resistance.

  • 10.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Electrolyte Solutions and Specific Ion Effects on Interfaces2013In: Journal of Chemical Education, ISSN 0021-9584, E-ISSN 1938-1328, Vol. 90, no 8, p. 1018-1023Article in journal (Refereed)
    Abstract [en]

    Introductory general and physical chemistry courses often deal with colligative properties of solutions and do not discuss nonideal solutions in detail. Yet, a growing body of evidence reveals that even at physiological concentrations electrolyte solutions cannot be treated as ideal when a charged or partially charged solute (such as a protein) is present in the solution. In such cases, the interactions between the salt ions and the solute depend on the specific ions that constitute the electrolyte solution (specific ion effects). For example, the catalytic efficiency of an enzyme may be different in NaCl and KCl solutions. In this article, specific ion effects are reviewed from a historical perspective, and then the current state of knowledge is presented at a qualitative level that is appropriate for second-year or advanced undergraduate science students. Finally, the related nomenclature (Bjerrum ion pairs, Hofmeister series, lyotropic series, and specific ion effects) is analyzed, and some suggestions are made with respect to the terminology, to make it more accessible to students. The material is appropriate for courses where solution chemistry is discussed, for example, in physical chemistry. In addition, it may be included in the chemistry curriculum for life or pharmaceutical sciences.

  • 11.
    Karlsson, Björn C. G.
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Olsson, Gustaf D.
    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.
    Rosengren, Annika M.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Henschel, Henning
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Division of Atmospheric Sciences, Department of Physics, University of Helsinki, P.O. Box 64, Helsinki, Finland.
    Nicholls, Ian A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    How warfarin’s structural diversity influences its phospholipid bilayer membrane permeation2013In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, no 8, p. 2384-2395Article in journal (Refereed)
    Abstract [en]

    The role of the structural diversity of the widely used anticoagulant drug warfarin on its distribution in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer membranes was investigated using a series of both restrained (umbrella sampling) and unrestrained molecular dynamics simulations. Data collected from unrestrained simulations revealed favorable positions for neutral isomers of warfarin, the open side chain form (OCO), and the cyclic hemiketal (CCO), along the bilayer normal close to the polar headgroup region and even in the relatively distant nonpolar lipid tails. The deprotonated open side chain form (DCO) was found to have lower affinity for the DOPC bilayer membrane relative to the neutral forms, with only a small fraction interacting with the membrane, typically within the polar headgroup region. The conformation of OCO inside the lipid bilayer was found to be stabilized by intramolecular hydrogen bonding thereby mimicking the structure of CCO. Differences in free energies, for positions of OCO and CCO inside the bilayer membrane, as compared to positions in the aqueous phase, were −97 and −146 kJ·mol–1. Kinetic analysis based on the computed free energy barriers reveal that warfarin will diffuse through the membranes within hours, in agreement with experimental results on warfarin’s accumulation in the plasma, thus suggesting a passive diffusion mechanism. We propose that this membrane transport may be an isomerization-driven process where warfarin adapts to the various local molecular environments encountered under its journey through the membrane. Collectively, these results improve our understanding of the influence of warfarin’s structural diversity on the drug’s distribution and bioavailability, which in turn may provide insights for developing new formulations of this important pharmaceutical to better address its narrow therapeutic window.

  • 12.
    Ahlstrand, Emma
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Spångberg, Daniel
    Uppsala University.
    Hermansson, Kersti
    Uppsala University.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Interaction energies between metal ions (Zn2+ and Cd2+) and biologically relevant ligands2013In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 113, no 23, p. 2554-2562Article in journal (Refereed)
    Abstract [en]

    Interactions between the group XII metals Zn2+ and Cd2+ and amino acid residues play an important role in biology due to the prevalence of the first and the toxicity of the second. Estimates of the interaction energies between the ions and relevant residues in proteins are however difficult to obtain. This study reports on calculated interaction energy curves for small complexes of Zn2+ or Cd2+ and amino acid mimics (acetate, methanethiolate, and imidazole) or water. Given that many applications and models (e.g., force fields, solvation models, etc.) begin with and rely on an accurate description of gas-phase interaction energies, this is where our focus lies in this study. Four density functional theory (DFT)-functionals and MP2 were used to calculate the interaction energies not only at the respective equilibrium distances but also at a relevant range of ion–ligand separation distances. The calculated values were compared with those obtained by CCSD(T). All DFT-methods are found to overestimate the magnitude of the interaction energy compared to the CCSD(T) reference values. The deviation was analyzed in terms of energy components from localized molecular orbital energy decomposition analysis scheme and is mostly attributed to overestimation of the polarization energy. MP2 shows good agreement with CCSD(T) [root mean square error (RMSE) = 1.2 kcal/mol] for the eight studied complexes at equilibrium distance. Dispersion energy differences at longer separation give rise to increased deviations between MP2 and CCSD(T) (RMSE = 6.4 kcal/mol at 3.0 Å). Overall, the results call for caution in applying DFT methods to metalloprotein model complexes even with closed-shell metal ions such as Zn2+ and Cd2+, in particular at ion–ligand separations that are longer than the equilibrium distances.

  • 13.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Boye, Kjetil
    Flatmark, Kjersti
    Molecular modelling and simulations in cancer research2013In: Biochimica et Biophysica Acta. CR. Reviews on Cancer, ISSN 0304-419X, E-ISSN 1879-2561, Vol. 1836, no 1, p. 1-14Article, review/survey (Refereed)
    Abstract [en]

    The complexity of cancer and the vast amount of experimental data available have made computer-aided approaches necessary. Biomolecular modelling techniques are becoming increasingly easier to use, whereas hardware and software are becoming better and cheaper. Cross-talk between theoretical and experimental scientists dealing with cancer-research from a molecular approach, however, is still uncommon. This is in contrast to other fields, such as amyloid-related diseases, where molecular modelling studies are widely acknowledged. The aim of this review paper is therefore to expose some of the more common approaches in molecular modelling to cancer scientists in simple terms, illustrating success stories while also revealing the limitations of computational studies at the molecular level.

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  • 14.
    Friedman, Ran
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Aggregation of amyloids in a cellular context: modelling and experiment2011In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 438, p. 415-426Article in journal (Refereed)
    Abstract [en]

    Amyloid-related diseases are a group of illnesses in which an abnormal accumulation of proteins into fibrillar structures is evident. Results from a wide range of studies, ranging from identification of amyloid-β dimers in the brain to biophysical characterization of the interactions between amyloidogenic peptides and lipid membranes during fibril growth shed light on the initial events which take place during amyloid aggregation. Accounts of fibril disaggregation and formation of globular aggregates due to interactions with lipids or fatty acids further demonstrate the complexity of the aggregation process and the difficulty to treat amyloid-related diseases. There is an inherent difficulty in generalizing from studies of aggregation in vitro, but the involvement of too many cellular components limits the ability to follow amyloid aggregation in a cellular (or extracellular) context. Fortunately, the development of experimental methods to generate stable globular aggregates suggests new means of studying the molecular events associated with amyloid aggregation. Furthermore, simulation studies enable deeper understanding of the experimental results and provide useful predictions that can be tested in the laboratory. Computer simulations can nowadays provide molecular or even atomistic details that are experimentally not available or very difficult to obtain. In the present review, recent developments on modelling and experiments of amyloid aggregation are reviewed, and an integrative account on how isolated interactions (as observed in vitro and in silico) combine during the course of amyloid-related diseases is presented. Finally, it is argued that an integrative approach is necessary to get a better understanding of the protein aggregation process.

  • 15.
    Friedman, Ran
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Ions and the protein surface revisited: extensive molecular dynamics simulations and analysis of protein structures in alkali-chloride solutions2011In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 115, p. 9213-9223Article in journal (Refereed)
    Abstract [en]

    Proteins interact with ions in various ways. The surface of proteins has an innate capability to bind ions, and it is also influenced by the screening of the electrostatic potential owing to the presence of salts in the bulk solution. Alkali metal ions and chlorides interact with the protein surface, but such interactions are relatively weak and often transient. In this paper, computer simulations and analysis of protein structures are used to characterize the interactions between ions and the protein surface. The results show that the ion-binding properties of protein residues are highly variable. For example, alkali metal ions are more often associated with aspartate residues than with glutamates, whereas chlorides are most likely to be located near arginines. When comparing NaCl and KCl solutions, it was found that certain surface residues attract the anion more strongly in NaCl. This study demonstrates that protein–salt interactions should be accounted for in the planning and execution of experiments and simulations involving proteins, particularly if subtle structural details are sought after.

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  • 16.
    Friedman, Ran
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Caflisch, Amedeo
    Department of Biochemistry, University of Zürich.
    Surfactant Effects on Amyloid Aggregation Kinetics2011In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 414, p. 303-312Article in journal (Refereed)
    Abstract [en]

    There is strong experimental evidence of the influence of surfactants (e.g., fatty acids) on the kinetics of amyloid fibril formation. However, the structures of mixed assemblies and interactions between surfactants and fibril-forming peptides are still not clear. Here, coarse-grained simulations are employed to study the aggregation kinetics of amyloidogenic peptides in the presence of amphiphilic lipids. The simulations show that the lower the fibril formation propensity of the peptides, the higher the influence of the surfactants on the peptide self-assembly kinetics. In particular, the lag phase of weakly aggregating peptides increases because of the formation of mixed oligomers, which are promoted by hydrophobic interactions and favorable entropy of mixing. A transient peak in the number of surfactants attached to the growing fibril is observed before reaching the mature fibril in some of the simulations. This peak originates from transient fibrillar defects consisting of exposed hydrophobic patches on the fibril surface, which provide a possible explanation for the temporary maximum of fluorescence observed sometimes in kinetic traces of the binding of small-molecule dyes to amyloid fibrils.

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  • 17. Seeber, M
    et al.
    Felline, A
    Raimondi, F
    Muff, S
    Friedman, Ran
    Univ Zurich, Dept Biochem, CH-8057 Zurich, Switzerland .
    Rao, F
    Caflisch, A
    Fanelli, F
    Wordom: a user-friendly program for the analysis of molecular conformations, trajectories, and free energy surfaces2011In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, no 6, p. 1183-1194Article in journal (Refereed)
  • 18.
    Friedman, Ran
    et al.
    University of Zürich, Switzerland.
    Caflisch, A
    On the orientation of the catalytic dyad in aspartic proteases2010In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 78, no 6, p. 1575-1582Article in journal (Refereed)
    Abstract [en]

    The recent re-refinement of the X-ray structure of apo plasmepsin II from Plasmodium falciparum suggests that the two carboxylate groups in the catalytic dyad are noncoplanar, (Robbins et al., Acta Crystallogr D Biol Crystallogr 2009;65: 294–296) in remarkable contrast with the vast majority of structures of aspartic proteases. Here, evidence for the noncoplanarity of the catalytic aspartates is provided by analysis of multiple explicit water molecular dynamics (MD) simulations of plasmepsin II, human β-secretase, and HIV-protease. In the MD runs of plasmepsin II, the angle between the planes of the two carboxylates of the catalytic dyad is almost always in the range 60°–120°, in agreement with the perpendicular orientation in the re-refined X-ray structure. The noncoplanar arrangement is prevalent also in the β-secretase simulations, as well as in the runs with the inhibitor-bound proteases. Quantum-mechanics calculations provide further evidence that before catalysis the noncoplanar arrangement is favored energetically in eukaryotic aspartic proteases. Remarkably, the coplanar orientation of the catalytic dyad is observed in MD simulations of HIV-protease at 100 K but not at 300 K, which indicates that the noncoplanar arrangement is favored by conformational entropy. This finding suggests that the coplanar orientation in the crystal structures of apo aspartic proteases is promoted by the very low temperature used for data collection (usually around 100 K).

  • 19.
    Friedman, Ran
    et al.
    University of Zürich, Switzerland.
    Pellarin, R
    Caflisch, A
    Soluble Protofibrils as Metastable Intermediates in Simulations of Amyloid Fibril Degradation Induced by Lipid Vesicles2010In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 1, no 2, p. 471-474Article in journal (Refereed)
1 - 19 of 19
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