Myosin V

Myosin V is a ubiquitous cellular ``motor'' powered by chemical energy stored in ATP molecules. Its well-known relative, myosin II, shortens the sarcomere in muscle contraction by pulling on actin filaments, with many myosin molecules working in coordination.  By contrast, individual myosin V molecules pair off into dimers, and perform linear motion much like we do – by walking.  While one motor domain remains bound firmly to a long actin track, the other takes a 36-nanometer step in search of its next binding site.  Once the leading motor is bound, the trailing motor dissociates from its track, and the cycle is repeated with the roles of the motors interchganged.  Myosin V dimers carry out essential intracellular transport, attaching to cellular organelles and membranes, and pulling them across micrometer distances toward the periphery of the cell.

Figure: Each myosin V molecule in a dimer possesses a globular motor domain to which a long lever arm is attached. The lever arm is followed by a dimerization region, and a cargo-binding domain. Inset: opening of the actin-binding cleft after the binding of new ATP.

Using Xray crystal structures as the starting point, we used an in silico microscope -- Restrained Targeted Molecular Dynamics computer simulation -- to examine, at the molecular level, the events that lead to the dissociation of a myosin V motor from the actin track upon the binding of one ATP molecule.  After Inserting the ATP into myosin's binding pocket and accelerating its closure by applying forces to a small number of atoms near the ATP, we were able to observe in slow

motion the propagation of these local changes through the entire myosin molecule.  Our results are fully consistent with experimental observations, and show directly how the events that occur near the ATP-binding pocket are translated into structural rearrangements far away: the opening of the actin-binding site to release myosin from actin, as well as motions that move the lever arm.  Although the simulations were performed using myosin V structures, the predictions

are likely to apply to other myosins as well, and can be tested in experiments by mutational analysis. 

The ultimate goals of the present research are to improve our understanding of how mechanical motion is created in cells.

Reference:

V. Ovchinnikov, B.L. Trout, and M. Karplus. Mechanical coupling in myosin V: A simulation study. J. Mol. Biol., 395:815–833, 2010. (preprint)