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Ahlstrand, E., Buetti-Dinh, A. & Friedman, R. (2018). An interactive computer lab of the galvanic cell for students in biochemistry. Biochemistry and molecular biology education, 46(1), 58-65
Open this publication in new window or tab >>An interactive computer lab of the galvanic cell for students in biochemistry
2018 (English)In: Biochemistry and molecular biology education, ISSN 1470-8175, E-ISSN 1539-3429, Vol. 46, no 1, p. 58-65Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
Wiley-Blackwell, 2018
National Category
Educational Sciences
Research subject
Natural Science, Science Education
Identifiers
urn:nbn:se:lnu:diva-69198 (URN)10.1002/bmb.21091 (DOI)000419876100007 ()29131508 (PubMedID)
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2018-01-30Bibliographically approved
Buetti-Dinh, A. & Friedman, R. (2018). Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK6. BMC Bioinformatics, 19, 1-13, Article ID 155.
Open this publication in new window or tab >>Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK6
2018 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, p. 1-13, article id 155Article in journal (Refereed) Published
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.

National Category
Bioinformatics and Systems Biology Biochemistry and Molecular Biology Cancer and Oncology
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-73804 (URN)10.1186/s12859-018-2145-y (DOI)000431025900001 ()29699481 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-07-11Bibliographically approved
Friedman, R. (2018). Membrane-Ion Interactions. Journal of Membrane Biology, 251(3), 453-460
Open this publication in new window or tab >>Membrane-Ion Interactions
2018 (English)In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 251, no 3, p. 453-460Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Molecular dynamics, Alkali ions, Specific ion effects, Quadrupole NMR, Na-32 NMR
National Category
Physical Chemistry Theoretical Chemistry Biophysics
Research subject
Chemistry, Physical Chemistry; Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-76951 (URN)10.1007/s00232-017-0010-y (DOI)000437103200015 ()29330605 (PubMedID)
Available from: 2018-07-19 Created: 2018-07-19 Last updated: 2018-07-19Bibliographically approved
Friedman, R. & Agmon, N. (2017). Charge Transfer in Proteins: In Celebration of Hemi Gutman's 80th Birthday. Israel Journal of Chemistry, 57(5), 355-356
Open this publication in new window or tab >>Charge Transfer in Proteins: In Celebration of Hemi Gutman's 80th Birthday
2017 (English)In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 5, p. 355-356Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
Wiley-Blackwell, 2017
National Category
Chemical Sciences
Research subject
Natural Science, Chemistry
Identifiers
urn:nbn:se:lnu:diva-64374 (URN)10.1002/ijch.201700007 (DOI)000401329000001 ()
Available from: 2017-05-24 Created: 2017-05-24 Last updated: 2017-07-18Bibliographically approved
Ahlstrand, E., Zukerman Schpector, J. & Friedman, R. (2017). Computer simulations of alkali-acetate solutions: Accuracy of the forcefields in difference concentrations. Journal of Chemical Physics, 147, 1-10, Article ID 194102.
Open this publication in new window or tab >>Computer simulations of alkali-acetate solutions: Accuracy of the forcefields in difference concentrations
2017 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 147, p. 1-10, article id 194102Article in journal (Refereed) Published
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.

National Category
Physical Chemistry Theoretical Chemistry
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-68822 (URN)10.1063/1.4985919 (DOI)
Funder
Swedish National Infrastructure for Computing (SNIC), 2016/1-518Swedish Research Council, 2014-04406
Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-11-22Bibliographically approved
Karlsson, B. C. G. & Friedman, R. (2017). Dilution of whisky - the molecular perspective. Scientific Reports, 7(6489)
Open this publication in new window or tab >>Dilution of whisky - the molecular perspective
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 6489Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
Keywords
Whisky, dilution, guaiacol
National Category
Physical Chemistry Theoretical Chemistry
Research subject
Chemistry, Biochemistry; Chemistry, Organic Chemistry; Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-67349 (URN)10.1038/s41598-017-06423-5 (DOI)000407863100001 ()
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC/2014-1-404 SNIC/2015-1-444
Available from: 2017-08-22 Created: 2017-08-22 Last updated: 2017-08-31Bibliographically approved
Ahlstrand, E., Hermansson, K. & Friedman, R. (2017). Interaction Energies in Complexes of Zn and Amino Acids: A Comparison of Ab Initio and Force Field Based Calculations. Journal of Physical Chemistry A, 121(13), 2643-2654
Open this publication in new window or tab >>Interaction Energies in Complexes of Zn and Amino Acids: A Comparison of Ab Initio and Force Field Based Calculations
2017 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 121, no 13, p. 2643-2654Article in journal (Refereed) Published
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.

National Category
Physical Chemistry
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-64303 (URN)10.1021/acs.jpca.6b12969 (DOI)000398880800014 ()28272891 (PubMedID)
Available from: 2017-05-24 Created: 2017-05-24 Last updated: 2017-05-24Bibliographically approved
Maganhi, S. H., Jensen, P., Caracelli, I., Schpector, J. Z., Froehling, S. & Friedman, R. (2017). Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein. Protein Science, 26(4), 870-879
Open this publication in new window or tab >>Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein
Show others...
2017 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 26, no 4, p. 870-879Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2017
Keywords
resistance mutations, molecular dynamics, protein-drug interactions, DFG motif
National Category
Biochemistry and Molecular Biology
Research subject
Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-64193 (URN)10.1002/pro.3135 (DOI)000398183800020 ()
Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2018-06-05Bibliographically approved
Becconi, O., Ahlstrand, E., Salis, A. & Friedman, R. (2017). Protein-ion Interactions: Simulations of Bovine Serum Albumin in Physiological Solutions of NaCl, KCl and LiCl. Israel Journal of Chemistry, 57(5), 403-412
Open this publication in new window or tab >>Protein-ion Interactions: Simulations of Bovine Serum Albumin in Physiological Solutions of NaCl, KCl and LiCl
2017 (English)In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 57, no 5, p. 403-412Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2017
Keywords
molecular dynamics ; specific ion effects; Hofmeister series
National Category
Theoretical Chemistry Biophysics Physical Chemistry
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-64375 (URN)10.1002/ijch.201600119 (DOI)000401329000007 ()
Projects
SNIC 2015/1-226SNIC 2016/1-222
Funder
National Supercomputer Centre (NSC), Sweden, SNIC 2015/1-226National Supercomputer Centre (NSC), Sweden, SNIC 2016/1-222
Available from: 2017-05-24 Created: 2017-05-24 Last updated: 2017-07-18Bibliographically approved
Friedman, R. (2017). The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib. Proteins: Structure, Function, and Bioinformatics, 85(11), 2143-2152
Open this publication in new window or tab >>The molecular mechanism behind resistance of the kinase FLT3 to the inhibitor quizartinib
2017 (English)In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 85, no 11, p. 2143-2152Article in journal (Refereed) Published
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.

Keywords
leukaemia, leukemia, cancer, kinase inhibition, kinase inhibitors, molecular dynamics
National Category
Theoretical Chemistry Biophysics Physical Chemistry
Research subject
Natural Science, Chemistry
Identifiers
urn:nbn:se:lnu:diva-68436 (URN)10.1002/prot.25368 (DOI)000412824900017 ()28799176 (PubMedID)
Projects
CAN 2015/387SNIC 2016/1–55SNIC 2016/1–222SNIC 2017/1–23
Funder
Swedish Cancer Society, CAN 2015/387
Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2018-02-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8696-3104

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