Journal
BIOPHYSICAL JOURNAL
Volume 86, Issue 6, Pages 3794-3803Publisher
CELL PRESS
DOI: 10.1529/biophysj.103.037390
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Funding
- NIAMS NIH HHS [AR39643, R01 AR035186, R01 AR039643, AR35186] Funding Source: Medline
- NIDDK NIH HHS [DK05195] Funding Source: Medline
- NIGMS NIH HHS [GM08336, T32 GM008336] Funding Source: Medline
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The back door has been proposed to bean 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.BeFx and Mg.ADP.V-i structures. Simulations revealed that the relaxation of AIDP and free Pi 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.BeFx-based simulation but not in the Mg.AIDP.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 O-18-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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