title: Mechanochemical coupling in the myosin motor domain. I. Insights from equilibrium active-site simulations.
abstract: Although the major structural transitions in molecular motors are often argued to couple to the binding of Adenosine triphosphate (ATP), the recovery stroke in the conventional myosin has been shown to be dependent on the hydrolysis of ATP. To obtain a clearer mechanistic picture for such "mechanochemical coupling" in myosin, equilibrium active-site simulations with explicit solvent have been carried out to probe the behavior of the motor domain as functions of the nucleotide chemical state and conformation of the converter/relay helix. In conjunction with previous studies of ATP hydrolysis with different active-site conformations and normal mode analysis of structural flexibility, the results help establish an energetics-based framework for understanding the mechanochemical coupling. It is proposed that the activation of hydrolysis does not require the rotation of the lever arm per se, but the two processes are tightly coordinated because both strongly couple to the open/close transition of the active site. The underlying picture involves shifts in the dominant population of different structural motifs as a consequence of changes elsewhere in the motor domain. The contribution of this work and the accompanying paper [] is to propose the actual mechanism behind these "population shifts" and residues that play important roles in the process. It is suggested that structural flexibilities at both the small and large scales inherent to the motor domain make it possible to implement tight couplings between different structural motifs while maintaining small free-energy drops for processes that occur in the detached states, which is likely a feature shared among many molecular motors. The significantly different flexibility of the active site in different X-ray structures with variable level arm orientations supports the notation that external force sensed by the lever arm may transmit into the active site and influence the chemical steps (nucleotide hydrolysis and/or binding).
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Haibo
authors.initials: H
authors.lastname: Yu
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cui
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004735:Energy Transfer / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D020409:Molecular Motor Proteins / Q000737:chemistry* / Q000502:physiology*; D009218:Myosins / Q000737:chemistry* / Q000502:physiology*; D011485:Protein Binding
chemical_list: D020409:Molecular Motor Proteins; D000255:Adenosine Triphosphate; D009218:Myosins