Detachment, futile cycling, and nucleotide pocket collapse in myosin-V stepping

Neville J. Boon and Rebecca B. Hoyle
Phys. Rev. E 91, 022717 – Published 25 February 2015
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Abstract

Myosin-V is a highly processive dimeric protein that walks with 36-nm steps along actin tracks, powered by coordinated adenosine triphosphate (ATP) hydrolysis reactions in the two myosin heads. No previous theoretical models of the myosin-V walk reproduce all the observed trends of velocity and run length with adenosine diphosphate (ADP), ATP and external forcing. In particular, a result that has eluded all theoretical studies based upon rigorous physical chemistry is that run length decreases with both increasing [ADP] and [ATP]. We systematically analyze which mechanisms in existing models reproduce which experimental trends and use this information to guide the development of models that can reproduce them all. We formulate models as reaction networks between distinct mechanochemical states with energetically determined transition rates. For each network architecture, we compare predictions for velocity and run length to a subset of experimentally measured values, and fit unknown parameters using a bespoke Monte Carlo simulated annealing optimization routine. Finally we determine which experimental trends are replicated by the best-fit model for each architecture. Only two models capture them all: one involving [ADP]-dependent mechanical detachment, and another including [ADP]-dependent futile cycling and nucleotide pocket collapse. Comparing model-predicted and experimentally observed kinetic transition rates favors the latter.

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  • Received 24 May 2014
  • Revised 4 December 2014

DOI:https://doi.org/10.1103/PhysRevE.91.022717

©2015 American Physical Society

Authors & Affiliations

Neville J. Boon1,2,* and Rebecca B. Hoyle1,3,†

  • 1Department of Mathematics, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom
  • 2Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
  • 3Mathematical Sciences, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom

  • *n.boon@imperial.ac.uk
  • r.b.hoyle@soton.ac.uk

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Issue

Vol. 91, Iss. 2 — February 2015

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