Kinesin motility driven by subdomain dynamics

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Abstract

The microtubule (MT)-associated motor protein kinesin utilizes its conserved ATPase head to achieve diverse motility characteristics. Despite considerable knowledge about how its ATPase activity and MT binding are coupled to the motility cycle, the atomic mechanism of the core events remain to be found. To obtain insights into the mechanism, we performed 38.5 microseconds of all-atom molecular dynamics simulations of kinesin-MT complexes in different nucleotide states. Local subdomain dynamics were found to be essential for nucleotide processing. Catalytic water molecules are dynamically organized by the switch domains of the nucleotide binding pocket while ATP is torsionally strained. Hydrolysis products are 'pulled' by switch-I, and a new ATP is "captured" by a concerted motion of the α0/L5/switch-I trio. The dynamic and wet kinesin-MT interface is tuned for rapid interactions while maintaining specificity. The resulting mechanism provides the flexibility necessary for walking in the crowded cellular environment.

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Wonmuk Hwang

Department of Biomedical Engineering, Texas A&M University, College Station, United States

For correspondence
hwm@tamu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7514-3186
Matthew Lang

Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, United States

For correspondence
matt.lang@vanderbilt.edu

Competing interests
The authors declare that no competing interests exist.
Martin Karplus

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States

For correspondence
marci@tammy.harvard.edu

Competing interests
The authors declare that no competing interests exist.

Funding

National Institutes of Health (R01GM087677)

Wonmuk Hwang
Matthew Lang

PIttsburgh Supercomputing Center (Anton Supercomputer)

Wonmuk Hwang
Martin Karplus

Texas A&M Supercomputing Facility

Wonmuk Hwang

Texas Advanced Computing Center

Wonmuk Hwang

CHARMM Development Project

Martin Karplus

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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