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

Detachment, futile cycling, and nucleotide pocket collapse in myosin-V stepping
Detachment, futile cycling, and nucleotide pocket collapse in myosin-V stepping
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.
1539-3755
Boon, Neville J.
31b46830-1376-493f-9071-4ff9bc240b2c
Hoyle, Rebecca B.
e980d6a8-b750-491b-be13-84d695f8b8a1
Boon, Neville J.
31b46830-1376-493f-9071-4ff9bc240b2c
Hoyle, Rebecca B.
e980d6a8-b750-491b-be13-84d695f8b8a1

Boon, Neville J. and Hoyle, Rebecca B. (2015) Detachment, futile cycling, and nucleotide pocket collapse in myosin-V stepping. Physical Review E, 91 (2). (doi:10.1103/PhysRevE.91.022717).

Record type: Article

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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More information

Submitted date: 24 May 2014
Accepted/In Press date: 4 December 2014
Published date: 25 February 2015
Organisations: Applied Mathematics

Identifiers

Local EPrints ID: 374800
URI: https://eprints.soton.ac.uk/id/eprint/374800
ISSN: 1539-3755
PURE UUID: 3d494b5d-ffd5-4c2d-99c6-2cdf24b689ff
ORCID for Rebecca B. Hoyle: ORCID iD orcid.org/0000-0002-1645-1071

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Date deposited: 03 Mar 2015 11:50
Last modified: 14 Mar 2019 01:37

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