Molecular origin of the weak susceptibility of kinesin velocity to loads and its relation to the collective behavior of kinesins
Qian Wang a, Michael R. Diehl b,c, Biman Jana d, Margaret S. Cheung a, e, Anatoly B. Kolomeisky a, b, c, and José N. Onuchic a, c, f, g, 1
Author Affiliations
Contributed by José N. Onuchic, September 2, 2017 (sent for review June 7, 2017; reviewed by Ioan Andricioaei and Garegin A. Papoian)
Fig. S3. Illustration of the ATP binding pocket defined in the simulation. The motor head is colored in cyan, and ATP is colored in yellow. The ATP binding pocket is defined as beads within 10 Å around the ATP surface, which are colored in red.
Significance
Successful functioning of biological systems depends on efficient cellular transport supported by several classes of active biological molecules known as motor proteins. Although they have been intensively studied using various experimental methods, their molecular properties remain not fully understood. We developed a theoretical approach by using structure-based molecular dynamics simulations. It allowed us to understand at the molecular level the effect of external forces on kinesin motor proteins. It is shown that a force-regulated coupling between the neck linker and the ATP binding site of a kinesin accounts for experimentally observed weak susceptibility to loads. Our framework helps us to rationalize the low cooperativity among kinesins. The presented method is a powerful tool in clarifying microscopic features of motor proteins.
Abstract
Motor proteins are active enzymatic molecules that support important cellular processes by transforming chemical energy into mechanical work. Although the structures and chemomechanical cycles of motor proteins have been extensively investigated, the sensitivity of a motor’s velocity in response to a force is not well-understood. For kinesin, velocity is weakly influenced by a small to midrange external force (weak susceptibility) but is steeply reduced by a large force. Here, we utilize a structure-based molecular dynamic simulation to study the molecular origin of the weak susceptibility for a single kinesin. We show that the key step in controlling the velocity of a single kinesin under an external force is the ATP release from the microtubule-bound head. Only under large loading forces can the motor head release ATP at a fast rate, which significantly reduces the velocity of kinesin. It underpins the weak susceptibility that the velocity will not change at small to midrange forces. The molecular origin of this velocity reduction is that the neck linker of a kinesin only detaches from the motor head when pulled by a large force. This prompts the ATP binding site to adopt an open state, favoring ATP release and reducing the velocity. Furthermore, we show that two load-bearing kinesins are incapable of equally sharing the load unless they are very close to each other. As a consequence of the weak susceptibility, the trailing kinesin faces the challenge of catching up to the leading one, which accounts for experimentally observed weak cooperativity of kinesins motors.
kinesin molecular mechanism susceptibility collective behavior
Footnotes
1To whom correspondence should be addressed. Email: jonuchic@rice.edu.
Author contributions: Q.W., M.S.C., A.B.K., and J.N.O. designed research; Q.W. performed research; Q.W., M.R.D., B.J., M.S.C., A.B.K., and J.N.O. analyzed data; and Q.W., M.R.D., B.J., M.S.C., A.B.K., and J.N.O. wrote the paper.
Reviewers: I.A., University of California, Irvine; and G.A.P., University of Maryland.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1710328114/-/DCSupplemental.
Copyright © 2017 the Author(s). Published by PNAS.
This is an open access article distributed under the PNAS license.
FREE PDF GRATIS: PNAS
