Computer simulation of the power stroke in muscle contraction
Final Report Abstract
The results obtained from the present work give a comprehensive picture of the mechanics of the recovery stroke and provide a detailed model for the coupling with ATPase activation which is consistent with the existing mutational data and explains the role of the highly conserved "wedging" loop. Since the converter domain is suspended on the relay and SHI helices, the successive and counter-clockwise seesaw motions of these two helices control the rotation of the converter domain in two stages. The present calculations also give new insights into how changes in the state of the nucleotide affect the structure around the ATP binding site. The reaction pathways for ATP hydrolysis, found in the catalytically competent closed/closed conformation of the Switch-l/Switch-2 loops of myosin, are all associative with a pentavalent bipyramidal oxyphosphorane transition state but can vary in the activation mechanism of the attacking water molecule. The coordination bond between the Mg2+ metal cofactor and Ser237 in the Switch-1 loop is broken in the product state, thereby facilitating the opening of the Switch-1 loop after hydrolysis is completed, which is required for subsequent strong rebinding to actin. These effects are instrumental in initiating the coupling mechanisms that make the Lymn-Taylor cycle functional.
Publications
- (2005) Structural mechanism of the recovery stroke in the myosin molecular motor. PNAS 102, 6873-6878
Fischer, S., Windshügel, B., Horak, D., Holmes, K. C. & Smith, J. C.
- (2006) Analyzing Large-Scale Structural Change in Proteins: Comparison of Principal Component Projection and Sammon Mapping Proteins. Structure, Function, and Bioinformatics 64, 210-218
Mesentean, S., Fischer, S. & Smith, J.C.
- (2006) Insights into the Chemomechanical Coupling of the Myosin Motor from simulation of its ATP hydrolysis mechanism. Biochemistry 45, 5830-5847
Schwarzl, S. M., Smith, J. C., & Fischer, S.
- (2006). Simulations of the myosin II motor reveal a nucleotide-state sensing element that controls the recovery stroke. Journal of Molecular Biology 361, 604-616
Koppole, S., Smith, J. C. & Fischer, S.
