Strain Mediated Adaptation Is Key for Myosin Mechanochemistry: Discovering General Rules for Motor Activity

A structure-based model of myosin motor is built in the same spirit of our early work for kinesin-1 and Ncd towards physical understanding of its mechanochemical cycle. We find a structural adaptation of the motor head domain in post-powerstroke state that signals faster ADP release from it compared to the same from the motor head in the pre-powerstroke state. For dimeric myosin, an additional forward strain on the trailing head, originating from the postponed powerstroke state of the leading head in the waiting state of myosin, further increases the rate of ADP release. This coordination between the two heads is the essence of the processivity of the cycle. Our model provides a structural description of the powerstroke step of the cycle as an allosteric transition of the converter domain in response to the Pi release. Additionally, the variation in structural elements peripheral to catalytic motor domain is the deciding factor behind diverse directionalities of myosin motors (myosin V & VI). Finally, we observe that there are general rules for functional molecular motors across the different families. Allosteric structural adaptation of the catalytic motor head in different nucleotide states is crucial for mechanochemistry. Strain-mediated coordination between motor heads is essential for processivity and the variation of peripheral structural elements is essential for their diverse functionalities.

本研究基于结构构建了肌球蛋白马达（myosin motor）的计算模型，其研究思路与我们此前针对驱动蛋白-1（kinesin-1）和Ncd开展的工作一脉相承，旨在从物理机制层面阐明其机械化学循环过程。我们发现，相较于前冲程（pre-powerstroke）状态下的马达头部结构，后冲程（post-powerstroke）状态下的马达头部结构域发生了适应性构象变化，可加速其腺苷二磷酸（ADP）的释放。对于二聚体肌球蛋白而言，处于等待状态的肌球蛋白先导头部处于延迟后冲程状态，由此对尾随头部产生额外的正向张力，可进一步提升ADP释放速率。两个头部之间的这种协同作用，是该循环持续行进能力的核心所在。我们的模型将该循环中的冲程步骤，阐释为转换器结构域（converter domain）响应无机磷酸（Pi）释放而发生的别构转换，从结构层面给出了对应描述。此外，催化马达结构域周边的结构元件的构象差异，是决定肌球蛋白马达（肌球蛋白V与肌球蛋白VI）具有不同运动方向性的关键因素。最后我们发现，不同家族的功能性分子马达均遵循通用的运作规律：催化马达头部在不同核苷酸结合状态下发生的别构构象适配，对其机械化学过程至关重要；马达头部之间由张力介导的协同作用，是实现持续行进能力的必要条件；而周边结构元件的构象差异，则是其实现多样化功能的核心基础。