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  • Title: Multiscale modeling of structural dynamics underlying force generation and product release in actomyosin complex.
    Author: Zheng W.
    Journal: Proteins; 2010 Feb 15; 78(3):638-60. PubMed ID: 19790263.
    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.
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