Multiscale modeling of structural dynamics underlying force generation and product release in actomyosin complex

Abstract

To decrypt the mechanistic basis of myosin motor function, it is essential to probe the conformational changes in actomyosin with high spatial and temporal resolutions. In a computational effort to meet this challenge, we have performed a multiscale modeling of the allosteric couplings and transition pathway of actomyosin complex by combining coarse-grained modeling of the entire complex with all-atom molecular dynamics simulations of the active site. Our modeling of allosteric couplings at the pre-powerstroke state has pinpointed key actin-activated couplings to distant myosin parts which are critical to force generation and the sequential release of phosphate and ADP. At the post-powerstroke state, we have identified isoform-dependent couplings which underlie the reciprocal coupling between actin binding and nucleotide binding in fast Myosin II, and load-dependent ADP release in Myosin V. Our modeling of transition pathway during powerstroke has outlined a clear sequence of structural events triggered by actin binding, which lead to subsequent force generation, twisting of central beta-sheet, and the sequential release of phosphate and ADP. Finally we have performed atomistic simulations of active-site dynamics based on an on-path "transition-state" myosin conformation, which has revealed significantly weakened coordination of phosphate by Switch II, and a disrupted key salt bridge between Switch I and II. Meanwhile, the coordination of MgADP by Switch I and P loop is less perturbed. As a result, the phosphate can be released prior to MgADP. This study has shed new lights on the controversy over the structural mechanism of actin-activated phosphate release and force generation in myosin motor.