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      Conformational distributions of isolated myosin motor domains encode their mechanochemical properties

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          Abstract

          Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it remains unclear how sequence encodes these differences, since biochemically distinct motors often have nearly indistinguishable crystal structures. We hypothesized that sequences produce distinct biochemical phenotypes by modulating the relative probabilities of an ensemble of conformations primed for different functional roles. To test this hypothesis, we modeled the distribution of conformations for 12 myosin motor domains by building Markov state models (MSMs) from an unprecedented two milliseconds of all-atom, explicit-solvent molecular dynamics simulations. Comparing motors reveals shifts in the balance between nucleotide-favorable and nucleotide-unfavorable P-loop conformations that predict experimentally measured duty ratios and ADP release rates better than sequence or individual structures. This result demonstrates the power of an ensemble perspective for interrogating sequence-function relationships.

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          Most cited references58

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          Python for Scientific Computing

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            The P-loop--a common motif in ATP- and GTP-binding proteins.

            Many ATP- and GTP-binding proteins have a phosphate-binding loop (P-loop), the primary structure of which typically consists of a glycine-rich sequence followed by a conserved lysine and a serine or threonine. The three-dimensional structures of several ATP- and GTP-binding proteins containing P-loops have now been solved. In this review current knowledge of P-loops is discussed with the additional aim of illustrating the fascinating relationship between protein sequence, structure and function.
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              Three-dimensional structure of myosin subfragment-1: a molecular motor.

              Directed movement is a characteristic of many living organisms and occurs as a result of the transformation of chemical energy into mechanical energy. Myosin is one of three families of molecular motors that are responsible for cellular motility. The three-dimensional structure of the head portion of myosin, or subfragment-1, which contains both the actin and nucleotide binding sites, is described. This structure of a molecular motor was determined by single crystal x-ray diffraction. The data provide a structural framework for understanding the molecular basis of motility.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                29 May 2020
                2020
                : 9
                : e55132
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine in St. Louis St. LouisUnited States
                [2 ]Center for the Science and Engineering of Living Systems, Washington University in St. Louis St. LouisUnited States
                National Heart, Lung and Blood Institute, National Institutes of Health United States
                National Heart, Lung and Blood Institute, National Institutes of Health United States
                National Heart, Lung and Blood Institute, National Institutes of Health United States
                Author information
                https://orcid.org/0000-0002-0340-951X
                http://orcid.org/0000-0002-5504-2684
                http://orcid.org/0000-0003-1320-3547
                https://orcid.org/0000-0002-2083-4892
                Article
                55132
                10.7554/eLife.55132
                7259954
                32479265
                a6abb14a-1d16-414a-bb3e-222aa78f4354
                © 2020, Porter et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 14 January 2020
                : 04 May 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01GM12400701
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01HL141086
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: T32GM02700
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: F30HL146052
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;
                Award ID: MCB-1552471
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
                Award ID: Career Award at the Scientific Interface
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000008, David and Lucile Packard Foundation;
                Award ID: Fellowship for Science and Engineering
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100009955, Monsanto Company;
                Award ID: Graduate Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100007268, Washington University in St. Louis;
                Award ID: Center for Biological Systems Engineering Fellowship
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Biochemistry and Chemical Biology
                Structural Biology and Molecular Biophysics
                Custom metadata
                Shifts in the balance between nucleotide-favorable and nucleotide-unfavorable conformations of myosin motors encode duty ratios and ADP release rates, demonstrating the power of an ensemble perspective for uncovering sequence-function relationships.

                Life sciences
                energy landscapes,machine learning,markov sate models,molecular dynamics,conformational heterogeneity,chicken,dictyostelium,human

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