A classical and Ab initio study of the interaction of the myosin triphosphate binding domain with ATP

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Abstract

We used classical molecular mechanics (MM) simulations and quantum mechanical (QM) structural relaxations to examine the active site of myosin when bound to ATP. Two conformations of myosin have been determined by x-ray crystallography. In one, there is no direct interaction between switch 2 and the nucleotide (open state). In the other (closed state), the universally conserved switch 2 glycine forms a hydrogen bond with a γ-phosphate oxygen. MM simulations indicate that the two states are thermodynamically stable and allow us to investigate the extent to which the P-loop, switch 1, and switch 2 are involved in hydrolysis. We find that the open structure has a higher affinity for ATP than the closed structure, and that ATP is distorted toward a transition state by interactions with the protein. We also examine how the structure of the binding site changes with either MgATP or CaATP as the nucleotide in myosin in the open conformer. Our analyses suggest that higher CaATPase rates occur because the leaving phosphate (Pi) group is more weakly bound and dissociation occurs faster. Finally, we validate the use of a particular formulation of a QM methodology (Car-Parrinello) to further refine the structures of the active site.

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Minehardt, T. J., Marzari, N., Cooke, R., Pate, E., Kollman, P. A., & Car, R. (2002). A classical and Ab initio study of the interaction of the myosin triphosphate binding domain with ATP. Biophysical Journal, 82(2), 660–675. https://doi.org/10.1016/S0006-3495(02)75429-5

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