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  • 1.
    Albet-Torres, Nuria
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Månsson, Alf
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Long-Term Storage of Surface-Adsorbed Protein Machines2011In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 11, p. 7108-7112Article in journal (Refereed)
    Abstract [en]

    The effective and simple long-term storage of complex functional proteins is critical in achieving commercially viable biosensors. This issue is particularly challenging in recently proposed types of nanobiosensors, where molecular-motor-driven transportation substitutes microfluidics and forms the basis for novel detection schemes. Importantly, therefore, we here describe that delicate heavy meromyosin (HMM)-based nanodevices (HMM motor fragments adsorbed to silanized surfaces and actin bound to HMM) fully maintain their function when stored at -20 degrees C for more than a month. The mechanisms for the excellent preservation of acto-HMM motor function upon repeated freeze thaw cycles are discussed. The results are important to the future commercial implementation of motor-based nanodevices and are of more general value to the long-term storage of any protein-based bionanodevice.

  • 2.
    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.

  • 3.
    Bengtsson, Elina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Persson, Malin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kumar, Saroj
    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.
    Actomyosin Interactions and Different Structural States of Actin Filaments2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 2, p. 480A-481AArticle in journal (Other academic)
  • 4.
    Bengtsson, Elina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Persson, Malin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Karolinska Institutet ; McGill Univ, Canada.
    Rahman, Mohammad A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Kumar, Saroj
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Delhi Technol Univ, India.
    Takatsuki, Hideyo
    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.
    Myosin-Induced Gliding Patterns at Varied [MgATP] Unveil a Dynamic Actin Filament2016In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 111, no 7, p. 1465-1477Article in journal (Refereed)
    Abstract [en]

    Actin filaments have key roles in cell motility but are generally claimed to be passive interaction partners in actin-myosin -based motion generation. Here, we present evidence against this static view based on an altered myosin-induced actin filament gliding pattern in an in vitro motility assay at varied [MgATP]. The statistics that characterize the degree of meandering of the actin filament paths suggest that for [MgATP] >= 0.25 mM, the flexural rigidity of heavy meromyosin (HMM)-propelled actin filaments is similar (without phalloidin) or slightly lower (with phalloidin) than that of HMM-free filaments observed in solution without surface tethering. When [MgATP] was reduced to <= 0.1 mM, the actin filament paths in the in vitro motility assay became appreciably more winding in both the presence and absence of phalloidin. This effect of lowered [MgATP] was qualitatively different from that seen when HMM was mixed with ATP-insensitive, N-ethylmaleimide-treated HMM (NEM-HMM; 25-30%). In particular, the addition of NEM-HMM increased a non-Gaussian tail in the path curvature distribution as well as the number of events in which different parts of an actin filament followed different paths. These effects were the opposite of those observed with reduced [MgATP]. Theoretical modeling suggests a 30-40% lowered flexural rigidity of the actin filaments at [MgATP] <= 0.1 mM and local bending of the filament front upon each myosin head attachment. Overall, the results fit with appreciable structural changes in the actin filament during actomyosin-based motion generation, and modulation of the actin filament mechanical properties by the dominating chemomechanical actomyosin state.

  • 5. Chase, P. Bryant
    et al.
    Hong, Seunghun
    Månsson, Alf
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Xiong, Peng
    Bionanotechnology and Nanomedicine2012In: Journal of Biomedicine and Biotechnology, ISSN 1110-7243, E-ISSN 1110-7251, Vol. 2012, p. Article ID 763967-Article in journal (Other academic)
  • 6.
    Cournia, Zoe
    et al.
    Academy of Athens, Greece.
    Allen, Toby W.
    University of California, USA ; RMIT University, Australia.
    Andricioaei, Ioan
    University of California, USA.
    Antonny, Bruno
    Université de Nice Sophia-Antipolis, France.
    Baum, Daniel
    Zuse Institute Berlin, Germany.
    Brannigan, Grace
    Rutgers University-Camden, USA.
    Buchete, Nicolae-Viorel
    University College Dublin, Ireland.
    Deckman, Jason T.
    University of California, USA.
    Delemotte, Lucie
    Temple University, USA.
    del Val, Coral
    University of Granada, Spain.
    Friedman, Ran
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Gkeka, Paraskevi
    Academy of Athens, Greece.
    Hege, Hans-Christian
    Zuse Institute Berlin, Germany.
    Hénin, Jérôme
    IBPC and CNRS, France.
    Kasimova,, Marina A.
    Université de Lorraine, France ; Lomonosov Moscow State University, Russia.
    Kolocouris, Antonios
    University of Athens, Greece.
    Klein, Michael L.
    Temple University, USA.
    Khalid, Syma
    University of Southampton, UK.
    Lemieux, M. Joanne
    University of Alberta, Canada.
    Lindow, Norbert
    Zuse Institute Berlin, Germany.
    Mahua, Roy
    University of California, USA.
    Selent, Jana
    Universitat Pompeu Fabra, Spain.
    Tarek, Mounir
    Université de Lorraine, France ; CNRS SRSMC, France.
    Tofoleanu, Florentina
    University College Dublin, Ireland.
    Stefano, Vanni
    Université de Nice Sophia-Antipolis, Greece.
    Sinisa, Urban
    Johns Hopkins University School of Medicine, USA.
    Wales, David J.
    University of Cambridge, UK.
    Smith, Jeremy C.
    Oak Ridge National Laboratory, USA.
    Bondar, Ana-Nicoleta
    Freie Universität Berlin, Germany.
    Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory2015In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 248, no 4, p. 611-640Article in journal (Refereed)
    Abstract [en]

    Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.

  • 7. Dashevskaya, S
    et al.
    Kopito, R B
    Friedman, Ran
    Tel Aviv University, Israel.
    Elbaum, M
    Epel, B L
    Diffusion of anionic and neutral GFP derivatives through plasmodesmata in epidermal cells of Nicotiana benthamiana2008In: ProtoplasmaArticle in journal (Refereed)
  • 8.
    Enaki, N. A.
    et al.
    Moldavian Acad Sci, Moldova.
    Koroli, V. I.
    Moldavian Acad Sci, Moldova.
    Bazgan, S.
    Moldavian Acad Sci, Moldova.
    Nistreanu, A.
    Moldavian Acad Sci, Moldova.
    Palistrant, S.
    Moldavian Acad Sci, Moldova.
    Bogoev, D.
    Moldavian Acad Sci, Moldova.
    Turcan, M.
    Moldavian Acad Sci, Moldova.
    Pislari, T.
    Moldavian Acad Sci, Moldova.
    Boshneaga, Y.
    Moldavian Acad Sci, Moldova.
    Lambropoulos, N.
    London S Bank Univ, UK.
    Patel, S.
    London S Bank Univ, UK.
    Khrennikov, Andrei
    Linnaeus University, Faculty of Technology, Department of Mathematics.
    Marinucci, M.
    FZI, Forschungszentrum Informat, Germany.
    Kwok, S. C.
    Santa Lucia Fdn, Italy.
    Pannese, L.
    Imaginary SRL, Italy.
    Arniani, M.
    Sigma Orionis, France.
    Torrenti, R.
    Sigma Orionis, France.
    Maslobrod, S.
    Moldavian Acad Sci, Moldova.
    Scherbakov, V.
    Moldavian Acad Sci, Moldova.
    Kuznetsov, E.
    Moldavian Acad Sci, Moldova.
    Moldovanu, I.
    Inst Neurol & Neurosurg, Moldova.
    Misic, O.
    Inst Neurol & Neurosurg, Moldova.
    Odobescu, S.
    Inst Neurol & Neurosurg, Moldova.
    Lupusor, A.
    Inst Neurol & Neurosurg, Moldova.
    Cernei, A.
    Inst Neurol & Neurosurg, Moldova.
    Vovc, V.
    Univ Med & Pharm Nicolae Testemitanu, Moldova.
    Arnaut, O.
    Univ Med & Pharm Nicolae Testemitanu, Moldova.
    Ciobanu, N.
    Univ Med & Pharm Nicolae Testemitanu, Moldova.
    Tuzlucov, P.
    Inst Oncol, Dept Radiotherapy, Moldova.
    Kernbach, S.
    Res Ctr Adv Robot & Environm Sci, Germany.
    Sorli, A.
    Assoc Dev Consciousness & Hlth, Slovenia.
    Anisimov, V.
    Moldavian Acad Sci, Moldova.
    Quantum Information Processes in Protein Microtubules of Brain Neurons2016In: 3rd International Conference on Nanotechnologies and Biomedical Engineering, 2016, p. 245-249Conference paper (Refereed)
    Abstract [en]

    We study biologically 'orchestrated' coherent quantum processes in collections of protein microtubules of brain neurons, which correlate with, and regulate, neuronal synaptic and membrane activity. In this situation the continuous Schrodinger evolution of each such process terminates in accordance with the specific Diosi-Penrose (DP) scheme of 'objective reduction' ('OR') of the quantum state. This orchestrated OR activity ('Orch OR') is taken to result in moments of conscious awareness and/or choice. We analyze Orch OR in light of advances and developments in quantum physics, computational neuroscience and quantum biology. Much attention is also devoted to the 'beat frequencies' of faster microtubule vibrations as a possible source of the observed electro-encephalographic ('EEG') correlates of consciousness.

  • 9.
    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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  • 10.
    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.

  • 11.
    Friedman, Ran
    Tel Aviv University, Israel.
    Myosin V movement: Lessons from molecular dynamics studies of IQ peptides in the lever arm2007In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 50, p. 14524-14536Article in journal (Refereed)
    Abstract [en]

    Myosin V moves along actin filaments by an arm-over-arm motion, known as the lever mechanism. Each of its arms is composed of six consecutive IQ peptides that bind light chain proteins, such as calmodulin or calmodulin-like proteins. We have employed a multistage approach in order to investigate the mechanochemical structural basis of the movement of myosin V from the budding yeast Saccharomyces cerevisiae. For that purpose, we previously carried out molecular dynamics simulations of the Mlc1p−IQ2 and the Mlc1p−IQ4 protein−peptide complexes, and the present study deals with the structures of the IQ peptides when stripped from the Mlc1p protein. We have found that the crystalline structure of the IQ2 peptide retains a stable rodlike configuration in solution, whereas that of the IQ4 peptide grossly deviates from its X-ray conformation exhibiting an intrinsic tendency to curve and bend. The refolding process of the IQ4 peptide is initially driven by electrostatic interactions followed by nonpolar stabilization. Its bending appears to be affected by the ionic strength, when ionic strength higher than 300 mM suppresses it from flexing. Considering that a poly-IQ sequence is the lever arm of myosin V, we suggest that the arm may harbor a joint, localized within the IQ4 sequence, enabling the elasticity of the neck of myosin V. Given that a poly-IQ sequence is present at the entire class of myosin V and the possibility that the yeast's myosin V molecule can exist either as a nonprocessive monomer or as a processive dimer depending on conditions (Krementsova, E. B., Hodges, A. R., Lu, H., and Trybus, K. M. (2006) J. Biol. Chem. 281, 6079−6086), our observations may account for a general structural feature for the myosins' arm embedded flexibility.

  • 12.
    Friedman, Ran
    University of Zürich, Switzerland.
    Proton Transfer on the Molecular Surface of Proteins and Model Systems2009In: Israel Journal of Chemistry, ISSN 0021-2148, Vol. 49, no 2, p. 149-153Article in journal (Refereed)
    Abstract [en]

    Proton transfer (PT) reactions take place oil the molecular Surface of proteins, membranes, ionic polymers, and other molecules. The rates of the reactions can be followed experimentally, while the atomistic details can be elucidated by molecular modeling. This manuscript gives a brief overview of the use of computer simulations and molecular modeling, in conjuction with experiments, to study PT reactions oil the surface of solvated molecules. An integrative approach is discussed, where molecular dynamics simulations are performed with a protein, and quantum-mechanics-based calculations are performed oil a small molecule. The simulation results allow the identification of the necessary conditions that yield PT reactions oil the molecular surface. The reactions are efficient when they involve a donor and acceptor located a few A apart and under the influence of a negative electrostatic field. In proton-pumping proteins, it is possible to identify such conditions a priori and locate proton-attracting antenna domains without the need to mutate each potential donor and acceptor. Based on density functional theory calculations, the arrangement of water molecules that interconnect the donor and acceptor moieties is suggested as the rate-limiting step for proton transfer on the molecular surface.

  • 13.
    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.

  • 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.

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  • 15. Friedman, Ran
    et al.
    Caflisch, A
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Pepsinogen-like activation intermediate of plasmepsin II revealed by molecular dynamics analysis2008In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 73, no 4, p. 814-827Article in journal (Refereed)
  • 16.
    Friedman, Ran
    et al.
    University of Zürich, Switzerland.
    Caflisch, A.
    The Protonation State of the Catalytic Aspartates in Plasmepsin II2007In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 581, p. 4120-4124Article in journal (Refereed)
  • 17.
    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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  • 18.
    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.

  • 19.
    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.

  • 20.
    Friedman, Ran
    et al.
    Tel Aviv University, Israel.
    Nachliel, E.
    Gutman, M.
    Application of Classical Molecular Dynamics for Evaluation of Proton Transfer Mechanism on a Protein2005In: Bioch. Bioph. Acta., Vol. 1710, p. 67-77Article in journal (Refereed)
  • 21.
    Friedman, Ran
    et al.
    Tel Aviv University, Israel.
    Nachliel, E.
    Gutman, M.
    Fatty Acid Binding Proteins - Same Structure but Different Binding Mechanisms?: Molecular Dynamics Simulations of Intestinal Fatty Acid Binding Protein2006In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 90, p. 1535-45Article in journal (Refereed)
  • 22.
    Friedman, Ran
    et al.
    Laser Laboratory for Fast Reactions in Biology, Department of Biochemistry, The George S. Wise Faculty for Life Sciences, Tel Aviv University, Tel Aviv, Israel.
    Nachliel, E.
    Gutman, M.
    Molecular Dynamics of a Protein Surface: Ion-Residues Interactions2005In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 89, no 2, p. 768-781Article in journal (Refereed)
    Abstract [en]

    Time-resolved measurements indicated that protons could propagate on the surface of a protein or a membrane by a special mechanism that enhanced the shuttle of the proton toward a specific site. It was proposed that a suitable location of residues on the surface contributes to the proton shuttling function. In this study, this notion was further investigated by the use of molecular dynamics simulations, where Na+ and Clare the ions under study, thus avoiding the necessity for quantum mechanical calculations. Molecular dynamics simulations were carried out using as a model a few Na+ and Cl ions enclosed in a fully hydrated simulation box with a small globular protein (the S6 of the bacterial ribosome). Three independent 10-ns-long simulations indicated that the ions and the protein's surface were in equilibrium, with rapid passage of the ions between the protein's surface and the bulk. However, it was noted that close to some domains the ions extended their duration near the surface, thus suggesting that the local electrostatic potential hindered their diffusion to the bulk. During the time frame in which the ions were detained next to the surface, they could rapidly shuttle between various attractor sites located under the electrostatic umbrella. Statistical analysis of the molecular dynamics and electrostatic potential/entropy consideration indicated that the detainment state is an energetic compromise between attractive forces and entropy of dilution. The similarity between the motion of free ions next to a protein and the proton transfer on the protein's surface are discussed.

  • 23.
    Friedman, Ran
    et al.
    Tel AViV UniVersity, Tel AViV, Israel.
    Nachliel, E.
    Tel AViV UniVersity, Tel AViV, Israel.
    Gutman, M.
    Tel AViV UniVersity, Tel AViV, Israel.
    Molecular Dynamics Simulations of the Adipocyte Lipid Binding Protein Reveal a Novel Entry Site for the Ligand2005In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 44, p. 4275-4283Article in journal (Refereed)
    Abstract [en]

    The adipocyte lipid binding protein (ALBP) binds fatty acids (FA) in a cavity that is inaccessible from the bulk. Therefore, the penetration of the FA necessitates conformational changes whose nature is still unknown. It was suggested that the lipid first enters through a “portal region” which consists of the αII helix and the adjacent tight turns. The initial event in the ligand binding must be the interaction of the lipid with the protein surface. To analyze this interaction, we have carried out three molecular dynamics simulations of the apo-ALBP, with a palmitate ion initially located at different positions near the protein surface. The simulation indicated that the ligand could adsorb to the protein in more than one location. Yet, in one case, the ligand managed to penetrate the protein by entering a newly formed cavity some 10 Å deep. The entry site is located near the N-terminus, at the junction between the loops connecting the β-strands. Further progression of the penetration seems to be arrested by the need for desolvation of the COOH end of the headgroup. Evolutionary analysis showed that amino acids in this entry site are well conserved. On the basis of these observations, we suggest that the ligand may enter the protein from a site other than the portal region. Furthermore, the rate-limiting step is proposed to be the desolvation of the FA polar headgroup.

  • 24.
    Friedman, Ran
    et al.
    Tel Aviv University, Tel Aviv, Israel.
    Nachliel, E.
    Tel Aviv University, Tel Aviv, Israel.
    Gutman, M.
    Tel Aviv University, Tel Aviv, Israel.
    Protein Surface - the Dynamics of the Interactions between Protein, Water and Small Solutes2005In: Journal of biological physics (Print), ISSN 0092-0606, E-ISSN 1573-0689, Vol. 31, no 3-4, p. 433-452Article in journal (Refereed)
    Abstract [en]

    Previous time resolved measurements had indicated that protons could propagate on the surface of a protein, or a membrane, by a special mechanism that enhances the shuttle of the proton towards a specific site [1]. It was proposed that a proper location of residues on the surface contributes to the proton shuttling function. In the present study, this notion was further investigated using molecular dynamics, with only the mobile charge replaced by Na+ and Cl ions. A molecular dynamics simulation of a small globular protein (the S6 of the bacterial ribosome) was carried out in the presence of explicit water molecules and four pairs of Na+ and Cl ions. A 10 ns simulation indicated that the ions and the protein's surface were in equilibrium, with rapid passage of the ions between the protein's surface and the bulk. Yet it was noted that, close to some domains, the ions extended their duration near the surface, suggesting that the local electrostatic potential prevented them from diffusing to the bulk. During the time frame in which the ions were detained next to the surface, they could rapidly shuttle between various attractor sites located under the electrostatic umbrella. Statistical analysis of molecular dynamics and electrostatic potential/entropy consideration indicated that the detainment state is an energetic compromise between attractive forces and entropy of dilution. The similarity between the motion of free ions next to a protein and the proton transfer on the protein's surface are discussed.

  • 25.
    Friedman, Ran
    et al.
    Tel Aviv University, Israel.
    Nachliel, Esther
    Tel Aviv University, Israel.
    Gutman, Menachem
    Tel Aviv University, Israel.
    Protein surface dynamics: Interaction with water and small solutes2005In: Journal of biological physics (Print), ISSN 0092-0606, E-ISSN 1573-0689, Vol. 31, no 3, p. 433-452Article in journal (Refereed)
    Abstract [en]

    Previous time resolved measurements had indicated that protons could propagate on the surface of a protein, or a membrane, by a special mechanism that enhances the shuttle of the proton towards a specific site [1]. It was proposed that a proper location of residues on the surface contributes to the proton shuttling function. In the present study, this notion was further investigated using molecular dynamics, with only the mobile charge replaced by Na+and Cl ions. A molecular dynamics simulation of a small globular protein (the S6 of the bacterial ribosome) was carried out in the presence of explicit water molecules and four pairs of Na+ and Cl ions. A 10 ns simulation indicated that the ions and the protein's surface were in equilibrium, with rapid passage of the ions between the protein's surface and the bulk. Yet it was noted that, close to some domains, the ions extended their duration near the surface, suggesting that the local electrostatic potential prevented them from diffusing to the bulk. During the time frame in which the ions were detained next to the surface, they could rapidly shuttle between various attractor sites located under the electrostatic umbrella. Statistical analysis of molecular dynamics and electrostatic potential/entropy consideration indicated that the detainment state is an energetic compromise between attractive forces and entropy of dilution. The similarity between the motion of free ions next to a protein and the proton transfer on the protein's surface are discussed.

  • 26.
    Friedman, Ran
    et al.
    Laser Laboratory for Fast Reactions in Biology, Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel.
    Nachliel, Esther
    Laser Laboratory for Fast Reactions in Biology, Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel.
    Gutman, Menachem
    Laser Laboratory for Fast Reactions in Biology, Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel.
    The role of small intraprotein cavities in the catalytic cycle of bacteriorhodopsin2003In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 85, no 2, p. 886-896Article in journal (Refereed)
    Abstract [en]

    The last phase of the proton transfer cycle of bacteriorhodopsin calls for a passage of a proton from D38 to D96.This reaction utilizes a narrow shaft ;10-A˚ long that connects the two carboxylates that cross through a very hydrophobicdomain. As the shaft is too narrow to be permanently hydrated, there are two alternatives for the proton propagation into thechannel. The proton may propagate through the shaft without solvation at the expense of a high electrostatic barrier;alternatively, the shaft will expand to accommodate some water molecules, thus lowering the Born energy for the insertion ofthe charge into the protein (B. Scha¨ tzler, N. A. Dencher, J. Tittor, D. Oesterhelt, S. Yaniv-Checover, E. Nachliel, and G. Gutman,2003, Biophys. J. 84:671–686). A comparative study of nine published crystal-structures of bacteriorhodopsin identified, next tothe shaft, microcavities in the protein whose position and surrounding atoms are common to the reported structures. Some ofthe cavities either shrink or expand during the photocycle. It is argued that the plasticity of the cavities provides a working spaceneeded for the transient solvation of the shaft, thus reducing the activation energy necessary for the solvation of the shaft. Thissuggestion is corroborated by the recent observations of Klink et al. (B. U. Klink, R. Winter, M. Engelhard, and I. Chizhov, 2002,Biophys. J. 83:3490–3498) that the late phases of the photocycle (t $ 1 ms) are strongly inhibited by external pressure.

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  • 27.
    Friedman, Ran
    et al.
    University of Zürich, Switzerland.
    Pellarin, R
    Caflisch, A
    Amyloid aggregation on lipid bilayers and its impact on membrane permeability2009In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 387, no 2, p. 407-415Article in journal (Refereed)
  • 28.
    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)
  • 29.
    Fromell, Karin
    et al.
    Uppsala University.
    Yang, Yi
    University of Gothenburg.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Bo
    Uppsala University.
    Berglin, Mattias
    Gothenburg University;RISE Res Inst Sweden Chem Mat & Surfaces.
    Elwing, Hans
    University of Gothenburg.
    Absence of conformational change in complement factor 3 and factor XII adsorbed to acrylate polymers is related to a high degree of polymer backbone flexibility2017In: Biointerphases, ISSN 1934-8630, E-ISSN 1559-4106, Vol. 12, no 2, article id 02D417Article in journal (Refereed)
    Abstract [en]

    In previous investigations, the authors have examined the adsorption of albumin, immunoglobulin, and fibrinogen to a series of acrylate polymers with different backbone and side-group flexibility. The authors showed that protein adsorption to acrylates with high flexibility, such as poly(lauryl methacrylate) (PLMA), tends to preserve native conformation. In the present study, the authors have continued this work by examining the conformational changes that occur during the binding of complement factor 3 (C3) and coagulation factor XII (FXII). Native C3 adsorbed readily to all solid surfaces tested, including a series of acrylate surfaces of varying backbone flexibility. However, a monoclonal antibody recognizing a "hidden" epitope of C3 (only exposed during C3 activation or denaturation) bound to the C3 on the rigid acrylate surfaces or on polystyrene (also rigid), but not to C3 on the flexible PLMA, indicating that varying degrees of conformational change had occurred with binding to different surfaces. Similarly, FXII was activated only on the rigid poly(butyl methacrylate) surface, as assessed by the formation of FXIIa-antithrombin (AT) complexes; in contrast, it remained in its native form on the flexible PLMA surface. The authors also found that water wettability hysteresis, defined as the difference between the advancing and receding contact angles, was highest for the PLMA surface, indicating that a dynamic change in the interface polymer structure may help protect the adsorbed protein from conformational changes and denaturation. (C) 2017 Author(s).

  • 30.
    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.

  • 31. Ganoth, A.
    et al.
    Nachliel, E.
    Friedman, Ran
    Tel AvivUniversity, Israel.
    Gutman, M.
    Molecular dynamics study of a calmodulin-like protein with an IQ peptide: spontaneous refolding of the protein around the peptide2006In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 64, no 1, p. 133-146Article in journal (Refereed)
  • 32. Ganoth, Assaf
    et al.
    Friedman, Ran
    Nachliel, Esther
    Gutman, Menachem
    A molecular dynamics study and free energy analysis of complexes between the Mlc1p protein and two IQ motif peptides2006In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 91, no 7, p. 2436-2450Article in journal (Refereed)
  • 33.
    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.

  • 34. Gutman, M.
    et al.
    Nachliel, E.
    Friedman, Ran
    Tel Aviv University, Israel .
    The dynamics of proton transfer between adjacent sites2006In: Photochemical and Photobiological Sciences, ISSN 1474-905X, E-ISSN 1474-9092, Vol. 5, p. 531-537Article in journal (Refereed)
  • 35. Gutman, M.
    et al.
    Nachliel, E.
    Friedman, Ran
    Tel Aviv University, Israel.
    The mechanism of proton transfer between adjacent sites on the molecular surface2006In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1757, p. 931-941Article in journal (Refereed)
  • 36.
    Henn, Arnon
    et al.
    Technion, Israel.
    Shneyer, Boris
    Technion, Israel.
    Ušaj, Marko
    Technion, Israel.
    Myosin 19 is an Outer Mitochondrial Membrane Motor and Effector of Starvation Induced Filopodia with Unique Kinetic Features2016In: Biophysical Journal Supplement 1, 2016, Vol. 110, p. 615a-616a, article id 3040-PosConference paper (Refereed)
    Abstract [en]

    The interaction between the actin cytoskeleton, myosin motors and their function in mitochondria dynamics, morphology and cellular localization is now beginning to emerge. A novel function for actin-based motors as regulators of cellular adaptations to stress, linking actin cytoskeleton remodelling to mitochondria dynamics. We reveal a novel function for myosin 19 in mitochondrial dynamics and localization during cellular response to glucose starvation. Ectopically expressed myosin 19 localizes with mitochondria at the tips of starvation-induced filopodia. Corollary to this, RNAi mediated knockdown of myosin 19 diminished their formation without evident effects on the mitochondrial network. We analyzed myosin 19 mitochondria interaction and demonstrated that it is uniquely anchored to the outer mitochondrial membrane (OMM) via a 30-residue motif, indicating that myosin 19 is a stably attached OMM molecular motor. To this end, we have purified myosin 19-3IQ motor domain construct. Myosin 19-3IQ featured characteristic actin-activated ATPase activity with moderate to slow turnover (kcat) and relatively tight KATPase. Our transient kinetics and steady state equilibrium binding experiments revealed that myosin 19-3IQ binds ATP and ADP with tight affinity that, to the best of our knowledge, have not yet been exhibited by any other myosins. We suspect that this feature allows myosin 19 to operate in a unique cellular environment that may be related to cellular stress conditions as we showed in our previous studies. The detailed knowledge of myosin 19 enzymatic adaptation will provide us with a quantitative working model of myosin 19, and will assist us to understand its cellular function. Our work reveals a novel function for myosin 19 in mitochondrial positioning during homeostasis and under stress conditions and broadens our understanding of the actin cytoskeleton- myosin -mitochondria interplay.

  • 37.
    Khrennikov, Andrei
    et al.
    Linnaeus University, Faculty of Technology, Department of Mathematics.
    Yurova, Ekaterina
    Linnaeus University, Faculty of Technology, Department of Mathematics.
    Automaton model of protein: Dynamics of conformational and functional states2017In: Progress in Biophysics and Molecular Biology, ISSN 0079-6107, E-ISSN 1873-1732, Vol. 130, no A, p. 2-14Article in journal (Refereed)
    Abstract [en]

    In this conceptual paper we propose to explore the analogy between ontic/epistemic description of quantum phenomena and interrelation between dynamics of conformational and functional states of proteins. Another new idea is to apply theory of automata to model the latter dynamics. In our model protein's behavior is modeled with the aid of two dynamical systems, ontic and epistemic, which describe evolution of conformational and functional states of proteins, respectively. The epistemic automaton is constructed from the ontic automaton on the basis of functional (observational) equivalence relation on the space of ontic states. This reminds a few approaches to emergent quantum mechanics in which a quantum (epistemic) state is treated as representing a class of prequantum (ontic) states. This approach does not match to the standard protein structure-function paradigm. However, it is perfect for modeling of behavior of intrinsically disordered proteins. Mathematically space of protein's ontic states (conformational states) is modeled with the aid of p-adic numbers or more general ultrametric spaces encoding the internal hierarchical structure of proteins. Connection with theory of p-adic dynamical systems is briefly discussed.

  • 38.
    Liljesson, Kenneth
    Växjö University, Faculty of Mathematics/Science/Technology, School of Mathematics and Systems Engineering.
    Analys, elimination och reduktion av negativa bieffekter vid användning av elektriska fält i syfte att orientera molekylära motorer2008Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The molecular motors of muscle are of potential interest in nanotechnology. These motors consist of the protein, myosin II interacting with actin filaments. It would be of interest to control the interaction between actin and myosin, e.g. in order to steer their direction of motion. Because these proteins are electrically charged their motion in a cell filled with a solution could potentially be controlled by an electric field. Here I have addressed several problems associated with experiments of this type. A main problem was found to be excessive heating of the solution. Another complication was electroosmotic flow and chemical reactions on the cell surface. The electric field can also cause electrophoretic motion of the proteins, which in some cases is undesired. The most effective way to reduce the heating of the solution was to keep the ratio between the cross sectional area of the cell and its cooling surfaces as small as possible. External cooling of the cell and keeping the ionic concentration in the solution as low as possible also prevented overheating. The electroosmotic flow could be stopped with agarose plugs at the cell openings and the surface reactions can probably be avoided if trimethylchlorosilane (TMCS) coated glass rather than nitrocellulose film is used for myosin adsorption. If electrophoretic motion turns out to be a problem it can be reduced/stopped with an electroosmotic flow in the opposite direction. A further conclusion of this study is that actin filaments may be oriented by relatively small field strengths whereas it can be necessary to use electric field strength of 1 MV/m or more to orient myosin. At this extremely high field strength the heat production, in a cell with a rectangular cross section, would probably will be to high. However, if a cell with a circular and very low cross sectional area, i.e. a capillary, is used the heating can possibly be held under an acceptable limit.

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  • 39.
    Lindberg, Frida W.
    et al.
    Lund University, Sweden.
    Norrby, Marlene
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rahman, Mohammad A.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Salhotra, Aseem
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Takatsuki, Hideyo
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jeppesen, Soren
    Lund University, Sweden.
    Linke, Heiner
    Lund University, Sweden.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Controlled Surface Silanization for Actin-Myosin and Biocompatibility of New Polymer Resists2018In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 34, no 30, p. 8777-8784Article in journal (Refereed)
    Abstract [en]

    Molecular motor-based nanodevices require organized cytoskeletal filament guiding along motility-promoting tracks, confined by motility-inhibiting walls. One way to enhance motility quality on the tracks, particularly in terms of filament velocity but also the fraction of motile filaments, is to optimize the surface hydrophobicity. We have investigated the potential to achieve this for the actin myosin II motor system on trimethylchlorosilane (TMCS)-derivatized SiO2 surfaces to be used as channel floors in nanodevices. We have also investigated the ability to supress motility on two new polymer resists, TU7 (for nanoimprint lithography) and CSAR 62 (for electron beam and deep UV lithography), to be used as channel walls. We developed a chemical-vapor deposition tool for silanizing SiO2 surfaces in a controlled environment to achieve different surface hydrophobicities (measured by water contact angle). In contrast to previous work, we were able to fabricate a wide range of contact angles by varying the silanization time and chamber pressure using only one type of silane. This resulted in a significant improvement of the silanization procedure, producing a predictable contact angle on the surface and thereby predictable quality of the heavy meromyosin (HMM)-driven actin motility with regard to velocity. We observed a high degree of correlation between the filament sliding velocity and contact angle in the range 10-86 degrees, expanding the previously studied range. We found that the sliding velocity on TU7 surfaces was superior to that on CSAR 62 surfaces despite similar contact angles. In addition, we were able to suppress the motility on both TU7 and CSAR 62 by plasma oxygen treatment before silanization. These results are discussed in relation to previously proposed surface adsorption mechanisms of HMM and their relationship to the water contact angle. Additionally, the results are considered for the development of actin-myosin based nanodevices with superior performance with respect to actin-myosin functionality.

  • 40.
    Mandal, Sudip
    et al.
    Indian Inst Technol Madras, India.
    Suriyanarayanan, Subramanian
    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.
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, India.
    Selective Sensing of the Biotinyl Moiety Using Molecularly Imprinted Polyaniline Nanowires2018In: Journal of the Electrochemical Society, ISSN 0013-4651, E-ISSN 1945-7111, Vol. 165, no 14, p. B669-B678Article in journal (Refereed)
    Abstract [en]

    A chemosensor for selective recognition of biotinyl moiety has been devised using electropolymerized film and tested against selective biotinylated targets. The sensor comprises biotin molecularly imprinted polymer (MIP) polymeric nanowires, as a recognition element, overlaid on gold-coated quartz transducers. The preparation of nanostructured MIPs and reference systems have been demonstrated using electrochemical copolymerization of the stabilized complex between the template (biotin), the functional monomer (4-aminobenzoic acid), and cross-linker (aniline) and/or sacrificial biotin-modified Al2O3 membrane. Density functional theoretical studies signify formation of a stable hydrogen-bonded complex of biotin with 4-aminobenzoic acid in the pre-polymerization mixture. Scanning electron microscope studies revealed uniformly grown and densely packed polyaniline hierarchical structures. Piezoelectric microgravimetry under flow injection analysis (FIA) conditions revealed selective binding of biotin methyl ester (BtOMe, 4) (79.89 +/- 2.17 Hz/mM) with imprinted polyaniline hierarchical structures over 10 fold higher than the non-imprinted counterpart. The detection limit of the MIP is 50 nM under optimized conditions. Particularly, the sensor selectively recognizes BtOMe from structural or functional analogues, such as thiamine (4.87 +/- 0.10 Hz/mM) and pyridoxamine (12.08 +/- 0.24 Hz/mM). Importantly, the MIP hierarchical structures were shown to be selective for biotinylated targets (biotin moiety labeled cytochrome C, dextran, oxytocin and obestatin). (C) 2018 The Electrochemical Society.

  • 41.
    Matusovsky, Oleg S.
    et al.
    McGill Univ, Canada.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Persson, Malin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. McGill Univ, Canada.
    Cheng, Yu-Shu
    McGill Univ, Canada.
    Rassier, Dilson E.
    McGill Univ, Canada.
    High-speed AFM reveals subsecond dynamics of cardiac thin filaments upon Ca2+ activation and heavy meromyosin binding2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 33, p. 16384-16393Article in journal (Refereed)
    Abstract [en]

    High-speed atomic force microscopy (HS-AFM) can be used to study dynamic processes with real-time imaging of molecules within 1- to 5-nm spatial resolution. In the current study, we evaluated the 3-state model of activation of cardiac thin filaments (cTFs) isolated as a complex and deposited on a mica-supported lipid bilayer. We studied this complex for dynamic conformational changes 1) at low and high [Ca2+] (pCa 9.0 and 4.5), and 2) upon myosin binding to the cTF in the nucleotide-free state or in the presence of ATP. HS-AFM was used to directly visualize the tropo-myosin-troponin complex and Ca2+-induced tropomyosin movements accompanied by structural transitions of actin monomers within cTFs. Our data show that cTFs at relaxing or activating conditions are not ultimately in a blocked or activated state, respectively, but rather the combination of states with a prevalence that is dependent on the [Ca2+] and the presence of weakly or strongly bound myosin. The weakly and strongly bound myosin induce similar changes in the structure of cTFs as confirmed by the local dynamical displacement of individual tropomyosin strands in the center of a regulatory unit of cTF at the relaxed and activation conditions. The displacement of tropomyosin at the relaxed conditions had never been visualized directly and explains the ability of myosin binding to TF at the relaxed conditions. Based on the ratios of nonactivated and activated segments within cTFs, we proposed a mechanism of tropomyosin switching from different states that includes both weakly and strongly bound myosin.

  • 42.
    Matusovsky, Oleg S.
    et al.
    McGill Univ, Canada.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Rassier, Dilson E.
    McGill Univ, Canada.
    Cooperativity of myosin II motors in the non-regulated and regulated thin filaments investigated with high-speed AFM2023In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 155, no 3, article id e202213190Article in journal (Refereed)
    Abstract [en]

    Skeletal myosins II are non-processive molecular motors that work in ensembles to produce muscle contraction while binding to the actin filament. Although the molecular properties of myosin II are well known, there is still debate about the collective work of the motors: is there cooperativity between myosin motors while binding to the actin filaments? In this study, we use high-speed AFM to evaluate this issue. We observed that the initial binding of small arrays of myosin heads to the non-regulated actin filaments did not affect the cooperative probability of subsequent bindings and did not lead to an increase in the fractional occupancy of the actin binding sites. These results suggest that myosin motors are independent force generators when connected in small arrays, and that the binding of one myosin does not alter the kinetics of other myosins. In contrast, the probability of binding of myosin heads to regulated thin filaments under activating conditions (at high Ca2+ concentration in the presence of 2 mu M ATP) was increased with the initial binding of one myosin, leading to a larger occupancy of available binding sites at the next half-helical pitch of the filament. The result suggests that myosin cooperativity is observed over five pseudo-repeats and defined by the activation status of the thin filaments. The activation status of thin filaments determines cooperativity between neighboring myosin heads in muscle.

  • 43.
    Meiby, Elinor
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    M Zetterberg, Malin
    Uppsala University.
    Victor, Hernàndez
    Uppsala University.
    Ohlson, Sten
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore.
    Edwards, Katarina
    Uppsala University.
    Immobilized lipodisks as model membranes in high-throughput HPLC-MS analysis.2013In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 405, no 14, p. 4859-4869Article in journal (Refereed)
    Abstract [en]

    Lipodisks, also referred to as polyethylene glycol (PEG)-stabilized bilayer disks, have previously been demonstrated to hold great potential as model membranes in drug partition studies. In this study, an HPLC-MS system with stably immobilized lipodisks is presented. Functionalized lipodisks were immobilized on two different HPLC support materials either covalently by reductive amination or by streptavidin-biotin binding. An analytical HPLC column with immobilized lipodisks was evaluated by analysis of mixtures containing 15 different drug compounds. The efficiency, reproducibility, and stability of the system were found to be excellent. In situ incorporation of cyclooxygenase-1 (COX-1) in immobilized lipodisks on a column was also achieved. Specific binding of COX-1 to the immobilized lipodisks was validated by interaction studies with QCM-D. These results, taken together, open up the possibility of studying ligand interactions with membrane proteins by weak affinity chromatography.

  • 44.
    Melkikh, Alexey V.
    et al.
    Ural Fed Univ, Russia.
    Khrennikov, Andrei
    Linnaeus University, Faculty of Technology, Department of Mathematics.
    Nontrivial quantum and quantum-like effects in biosystems: Unsolved questions and paradoxes2015In: Progress in Biophysics and Molecular Biology, ISSN 0079-6107, E-ISSN 1873-1732, Vol. 119, no 2, p. 137-161Article, review/survey (Refereed)
    Abstract [en]

    Non-trivial quantum effects in biological systems are analyzed. Some unresolved issues and paradoxes related to quantum effects (Levinthal's paradox, the paradox of speed, and mechanisms of evolution) are addressed. It is concluded that the existence of non-trivial quantum effects is necessary for the functioning of living systems. In particular, it is demonstrated that classical mechanics cannot explain the stable work of the cell and any over-cell structures. The need for quantum effects is generated also by combinatorial problems of evolution. Their solution requires a priori information about the states of the evolving system, but within the framework of the classical theory it is not possible to explain mechanisms of its storage consistently. We also present essentials of so called quantum-like paradigm: sufficiently complex bio-systems process information by violating the laws of classical probability and information theory. Therefore the mathematical apparatus of quantum theory may have fruitful applications to describe behavior of bio-systems: from cells to brains, ecosystems and social systems. In quantum-like information biology it is not presumed that quantum information bio-processing is resulted from quantum physical processes in living organisms. Special experiments to test the role of quantum mechanics in living systems are suggested. This requires a detailed study of living systems on the level of individual atoms and molecules. Such monitoring of living systems in vivo can allow the identification of the real potentials of interaction between biologically important molecules. (C) 2015 Elsevier Ltd. All rights reserved.

  • 45. Mezer, A.
    et al.
    Friedman, Ran
    Tel Aviv University, Israel.
    Noivirt, O.
    Nachliel, E.
    Gutman, M.
    The mechanism of proton transfer between adjacent sites exposed to water2005In: J. Chem. Phys. B, Vol. 109, p. 11379-11388Article in journal (Refereed)
  • 46.
    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.

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  • 47.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Actomyosin based contraction: one mechanokinetic model from single molecules to muscle?2016In: Journal of Muscle Research and Cell Motility, ISSN 0142-4319, E-ISSN 1573-2657, Vol. 37, no 6, p. 181-194Article in journal (Refereed)
    Abstract [en]

    Bridging the gaps between experimental systems on different hierarchical scales is needed to overcome remaining challenges in the understanding of muscle contraction. Here, a mathematical model with well-characterized structural and biochemical actomyosin states is developed to that end. We hypothesize that this model accounts for generation of force and motion from single motor molecules to the large ensembles of muscle. In partial support of this idea, a wide range of contractile phenomena are reproduced without the need to invoke cooperative interactions or ad hoc states/transitions. However, remaining limitations exist, associated with ambiguities in available data for model definition e.g.: (1) the affinity of weakly bound cross-bridges, (2) the characteristics of the cross-bridge elasticity and (3) the exact mechanistic relationship between the force-generating transition and phosphate release in the actomyosin ATPase. Further, the simulated number of attached myosin heads in the in vitro motility assay differs several-fold from duty ratios, (fraction of strongly attached ATPase cycle times) derived in standard analysis. After addressing the mentioned issues the model should be useful in fundamental studies, for engineering of myosin motors as well as for studies of muscle disease and drug development.

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  • 48.
    Månsson, Alf
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Actomyosin-ADP states, interhead cooperativity, and the force-velocity relation of skeletal muscle.2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 98, no 7, p. 1237-1246Article in journal (Refereed)
    Abstract [en]

    Despite intense efforts to elucidate the molecular mechanisms that determine the maximum shortening velocity and the shape of the force-velocity relationship in striated muscle, our understanding of these mechanisms remains incomplete. Here, this issue is addressed by means of a four-state cross-bridge model with significant explanatory power for both shortening and lengthening contractions. Exploration of the parameter space of the model suggests that an actomyosin-ADP state (AM( *)ADP) that is separated from the actual ADP release step by a strain-dependent isomerization is important for determining both the maximum shortening velocity and the shape of the force-velocity relationship. The model requires a velocity-dependent, cross-bridge attachment rate to account for certain experimental findings. Of interest, the velocity dependence for shortening contraction is similar to that for population of the AM( *)ADP state (with a velocity-independent attachment rate). This accords with the idea that attached myosin heads in the AM( *)ADP state position the partner heads for rapid attachment to the next site along actin, corresponding to the apparent increase in attachment rate in the model.

  • 49.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    ATP-Driven Mechanical Work Performed by Molecular Motors2013In: Encyclopedia of Biophysics / [ed] Gordon C. K. Roberts, Springer, 2013, p. 135-141Chapter in book (Other academic)
  • 50.
    Månsson, Alf
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Linnaeus University, Linnaeus Knowledge Environments, Advanced Materials.
    Comparing models with one versus multiple myosin-binding sites per actin target zone: The power of simplicity2019In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 151, no 4, p. 578-592Article in journal (Refereed)
    Abstract [en]

    Mechanokinetic statistical models describe the mechanisms of muscle contraction on the basis of the average behavior of a large ensemble of actin-myosin motors. Such models often assume that myosin II motor domains bind to regularly spaced, discrete target zones along the actin-based thin filaments and develop force in a series of strain-dependent transitions under the turnover of ATP. The simplest models assume that there is just one myosin-binding site per target zone and a uniform spatial distribution of the myosin motor domains in relation to each site. However, most of the recently developed models assume three myosin-binding sites per target zone, and some models include a spatially explicit 3-D treatment of the myofilament lattice and thereby of the geometry of the actin-myosin contact points. Here, I show that the predictions for steady-state contractile behavior of muscle are very similar whether one or three myosin-binding sites per target zone is assumed, provided that the model responses are appropriately scaled to the number of sites. Comparison of the model predictions for isometrically contracting mammalian muscle cells suggests that each target zone contains three or more myosin-binding sites. Finally, I discuss the strengths and weaknesses of one-site spatially inexplicit models in relation to three-site models, including those that take into account the detailed 3-D geometry of the myofilament lattice. The results of this study suggest that single-site models, with reduced computational cost compared with multisite models, are useful for several purposes, e.g., facilitated molecular mechanistic insights.

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