Myosin-V步进中的分离、无效循环和核苷酸袋塌陷
Detachment, Futile Cycling and Nucleotide Pocket Collapse in Myosin-V Stepping
摘要：
肌球蛋白-V是一种高度进行性的二聚体蛋白，其沿着肌动蛋白轨道以36 nm的步长行走，由两个肌球蛋白头部中协调的ATP水解反应提供动力。没有以前的理论模型的肌球蛋白V行走再现所有观察到的趋势的速度和运行长度与[ADP]，[ATP]和外部强迫。特别是，所有基于严格物理化学的理论研究都无法得到的一个结果是，游程长度随着[ADP]和[ATP]的增加而减少。我们系统地分析了现有模型中的哪些机制再现了哪些实验趋势，并利用这些信息来指导模型的开发。我们制定模型之间的反应网络不同的机械化学状态与能量确定的过渡率。对于每种网络架构，我们将速度和运行长度的预测与实验测量值的子集进行比较，并使用定制的MCSA优化程序拟合未知参数。最后，我们确定哪些实验趋势是由每个架构的最佳拟合模型复制的。只有两个模型捕捉到了它们：一个涉及[ADP]依赖的机械脱离，另一个包括[ADP]依赖的无效循环和核苷酸口袋崩溃。比较模型预测和实验观察到的动力学转变速率有利于后者。
英文摘要：
Myosin-V is a highly processive dimeric protein that walks with 36nm steps along actin tracks, powered by coordinated ATP hydrolysis reactions in the two myosin heads. No previous theoretical models of the myosin-V walk reproduce all the observed trends of velocity and run-length with [ADP], [ATP] and external forcing. In particular, a result that has eluded all theoretical studies based upon rigorous physical chemistry is that run length decreases with both increasing [ADP] and [ATP]. We systematically analyse which mechanisms in existing models reproduce which experimental trends and use this information to guide the development of models that can reproduce them all. We formulate models as reaction networks between distinct mechanochemical states with energetically determined transition rates. For each network architecture, we compare predictions for velocity and run length to a subset of experimentally measured values, and fit unknown parameters using a bespoke MCSA optimization routine. Finally we determine which experimental trends are replicated by the best-fit model for each architecture. Only two models capture them all: one involving [ADP]-dependent mechanical detachment, and another including [ADP]-dependent futile cycling and nucleotide pocket collapse. Comparing model-predicted and experimentally observed kinetic transition rates favors the latter.
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