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      Modeling the Actin.myosin ATPase Cross-Bridge Cycle for Skeletal and Cardiac Muscle Myosin Isoforms

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          Abstract

          Modeling the complete actin.myosin ATPase cycle has always been limited by the lack of experimental data concerning key steps of the cycle, because these steps can only be defined at very low ionic strength. Here, using human β-cardiac myosin-S1, we combine published data from transient and steady-state kinetics to model a minimal eight-state ATPase cycle. The model illustrates the occupancy of each intermediate around the cycle and how the occupancy is altered by changes in actin concentration for [actin] = 1–20 K m . The cycle can be used to predict the maximal velocity of contraction (by motility assay or sarcomeric shortening) at different actin concentrations (which is consistent with experimental velocity data) and predict the effect of a 5 pN load on a single motor. The same exercise was repeated for human α-cardiac myosin S1 and rabbit fast skeletal muscle S1. The data illustrates how the motor domain properties can alter the ATPase cycle and hence the occupancy of the key states in the cycle. These in turn alter the predicted mechanical response of the myosin independent of other factors present in a sarcomere, such as filament stiffness and regulatory proteins. We also explore the potential of this modeling approach for the study of mutations in human β-cardiac myosin using the hypertrophic myopathy mutation R453C. Our modeling, using the transient kinetic data, predicts mechanical properties of the motor that are compatible with the single-molecule study. The modeling approach may therefore be of wide use for predicting the properties of myosin mutations.

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          Author and article information

          Contributors
          Journal
          Biophys J
          Biophys. J
          Biophysical Journal
          The Biophysical Society
          0006-3495
          1542-0086
          14 March 2017
          14 March 2017
          : 112
          : 5
          : 984-996
          Affiliations
          [1 ]Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts
          [2 ]Faculty of Science, University of Kragujevac, Kragujevac, Serbia
          [3 ]Department of Biosciences, University of Kent, Canterbury, Kent, United Kingdom
          [4 ]Department of Mechanical Engineering, Wentworth Institute of Technology, Boston, Massachusetts
          Author notes
          []Corresponding author smijailo@ 123456gmail.com
          [∗∗ ]Corresponding author m.a.geeves@ 123456kent.ac.uk
          Article
          PMC5355499 PMC5355499 5355499 S0006-3495(17)30120-0
          10.1016/j.bpj.2017.01.021
          5355499
          28297657
          © 2017 Biophysical Society.
          Categories
          Molecular Machines, Motors, and Nanoscale Biophysics

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