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Molecular Dynamics Analysis of Structural Factors Influencing Back Door P_i Release in Myosin

J. David Lawson ^*, Edward Pate , Ivan Rayment  and Ralph G. Yount ^* 

^* School of Molecular Biosciences, Department of Chemistry, and Department of Mathematics, Washington State University, Pullman, Washington 99164; and Department of Biochemistry and Institute for Enzyme Research, University of Wisconsin Madison, Madison, Wisconsin 53705

Correspondence: Address reprint requests to Ralph G. Yount, Tel.: 509-335-3442; Fax: 509-335-9688; E-mail: yount{at}wsu.edu.

The back door has been proposed to be an exit pathway from the myosin active site for phosphate (P_i) generated by adenosine 5'-triphosphate hydrolysis. We used molecular dynamics simulations to investigate the interaction of P_i with the back door and the plausibility of P_i release via this route. Molecular dynamics simulations were performed on the Dictyostelium motor domain with bound Mg·adenosine 5'-diphosphate (ADP) and P_i, modeled upon the Mg·ADP·BeF_x and Mg·ADP·V_i structures. Simulations revealed that the relaxation of ADP and free P_i from their initial positions reduced the diameter of the back door via motions of switch 1 and switch 2 located in the upper and lower 50-kDa subdomains, respectively. In neither simulation could P_i freely diffuse out the back door. Water molecules, however, could flux through the back door in the Mg·ADP·BeF_x-based simulation but not in the Mg·ADP·V_i-based simulation. In neither structure was water observed fluxing through the main (front door) entrance. These observations suggest that the ability of P_i to leave via the back door is linked tightly to conformational changes between the upper and lower 50-kDa subdomains. The simulations offer structural explanations for ¹⁸O-exchange with P_i at the active site, and P_i release being the rate-limiting step in the myosin adenosine 5'-triphosphatase.

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