The contraction of striated muscle is driven by cycling myosin motor proteins embedded within the thick filaments of sarcomeres. In addition to cross-bridge cycling with actin, these myosin proteins can enter an inactive, sequestered state in which the globular S1 heads rest along the thick filament surface and are inhibited from performing motor activities. Structurally, this state is called the interacting heads motif (IHM) and is a critical conformational state of myosin that regulates muscle contractility and energy expenditure. Structural perturbation of the sequestered state can pathologically disrupt IHM structure and the mechanical performance of muscle tissue. Thus, the IHM state has become a target for therapeutic intervention. An ATP analog called 2′-deoxy-ATP (dATP) is a potent myosin activator that destabilizes the IHM. Here, we use molecular dynamics simulations to study the molecular mechanisms by which dATP modifies the structure and dynamics of myosin in a sequestered state. Simulations of the IHM state containing ADP.Pi in both nucleotide binding pockets revealed dynamic motions of the blocked head-free head interface, light chain binding domain, and S2 in this “inactive” state of myosin. Replacement of ADP.Pi by dADP.Pi triggered a series of structural changes that increased heterogeneity among residue contact pairs at the blocked head-free head interface and a 14% decrease in the interaction energy at the interface. Dynamic changes to this interface were accompanied by dynamics in the light chain binding region. A comparative analysis of these dynamics predicted new structural sites that may affect IHM stability.

中文翻译：

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相互作用的肌球蛋白头部动力学及其 2′-脱氧-ADP 的修饰


横纹肌的收缩是由嵌入肌节粗丝内的循环肌球蛋白运动蛋白驱动的。除了与肌动蛋白的跨桥循环外，这些肌球蛋白还可以进入非活性、隔离状态，在这种状态下，球状 S1 头沿着粗丝表面停留并受到抑制进行运动活动。在结构上，这种状态称为相互作用的头部基序 （IHM），是肌球蛋白的一种关键构象状态，可调节肌肉收缩力和能量消耗。隔离状态的结构扰动会病理性地破坏 IHM 结构和肌肉组织的机械性能。因此，IHM 状态已成为治疗干预的目标。一种称为 2′-脱氧 ATP （dATP） 的 ATP 类似物是一种有效的肌球蛋白激活剂，可破坏 IHM 的稳定性。在这里，我们使用分子动力学模拟来研究 dATP 在隔离状态下改变肌球蛋白结构和动力学的分子机制。包含 ADP 的 IHM 状态的模拟。两个核苷酸结合口袋中的 Pi 揭示了阻塞的无头头界面、轻链结合结构域和 S2 在这种肌球蛋白“非活性”状态下的动态运动。替代 ADP。Pi by dADP.Pi 触发了一系列结构变化，这些变化增加了阻塞的无头头界面处残基接触对之间的异质性，界面处的相互作用能降低了 14%。此界面的动态变化伴随着轻链绑定区域中的动态。对这些动力学的比较分析预测了可能影响 IHM 稳定性的新结构位点。