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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
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
Keyword
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
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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
Keyword
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: 2018-02-06Bibliographically 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
Keyword
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.

Keyword
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
Katona, G., Lundholm, I., Rodilla, H., Garcia-Bonete, M.-J., Duelli, A., Wahlgren, W. Y., . . . Stake, J. (2016). Bayesian analysis of non-thermal structural changes induced by terahertz radiation in protein crystals. In: 2016 41ST INTERNATIONAL CONFERENCE ON INFRARED, MILLIMETER, AND TERAHERTZ WAVES (IRMMW-THZ): . Paper presented at 41st International Conference on Infrared, Millimeter, and Terahertz waves (IRMMW-THz), Copenhagen, DENMARK, SEP 25-30 2016. IEEE conference proceedings
Open this publication in new window or tab >>Bayesian analysis of non-thermal structural changes induced by terahertz radiation in protein crystals
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2016 (English)In: 2016 41ST INTERNATIONAL CONFERENCE ON INFRARED, MILLIMETER, AND TERAHERTZ WAVES (IRMMW-THZ), IEEE conference proceedings, 2016Conference paper, Published 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.

Place, publisher, year, edition, pages
IEEE conference proceedings, 2016
Series
International Conference on Infrared Millimeter and Terahertz Waves, ISSN 2162-2027
National Category
Structural Biology Physical Chemistry
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-60626 (URN)10.1109/IRMMW-THz.2016.7758457 (DOI)000391406200119 ()2-s2.0-85006142642 (Scopus ID)978-1-4673-8485-8 (ISBN)
Conference
41st International Conference on Infrared, Millimeter, and Terahertz waves (IRMMW-THz), Copenhagen, DENMARK, SEP 25-30 2016
Available from: 2017-02-10 Created: 2017-02-10 Last updated: 2017-02-21Bibliographically approved
Pineda De Castro, L. F., Dopson, M. & Friedman, R. (2016). Biological Membranes in Extreme Conditions: Anionic Tetraether Lipid Membranes and Their Interactions with Sodium and Potassium. Journal of Physical Chemistry B, 120(41), 10628-10634
Open this publication in new window or tab >>Biological Membranes in Extreme Conditions: Anionic Tetraether Lipid Membranes and Their Interactions with Sodium and Potassium
2016 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, no 41, p. 10628-10634Article in journal (Refereed) Published
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.

National Category
Theoretical Chemistry Physical Chemistry
Research subject
Chemistry, Physical Chemistry
Identifiers
urn:nbn:se:lnu:diva-57493 (URN)10.1021/acs.jpcb.6b06206 (DOI)000386107500002 ()2-s2.0-84992197879 (Scopus ID)
Funder
Carl Tryggers foundation , 11:146Carl Tryggers foundation , 12:140Swedish National Infrastructure for Computing (SNIC)
Available from: 2016-10-20 Created: 2016-10-20 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8696-3104

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