PDF(Pubmed)
Abstract：
Hypertrophic cardiomyopathy is one of the most common forms of genetic cardiomyopathy. Mavacamten is a first-in-class myosin modulator that was identified via activity screening on the wild type, and it is FDA-approved for the treatment of obstructive hypertrophic cardiomyopathy (HCM). The drug selectively binds to the cardiac β-myosin, inhibiting myosin function to decrease cardiac contractility. Though the drug is thought to affect multiple steps of the myosin cross-bridge cycle, its detailed mechanism of action is still under investigation. Individual steps in the overall cross-bridge cycle must be queried to elucidate the full mechanism of action. In this study, we utilize the rare-event method of transition path sampling to generate reactive trajectories to gain insights into the action of the drug on the dynamics and rate of the ATP hydrolysis step for human cardiac β-myosin. We study three known HCM causative myosin mutations: R453C, P710R, and R712L to observe the effect of the drug on the alterations caused by these mutations in the chemical step. Since the crystal structure of the drug-bound myosin was not available at the time of this work, we created a model of the drug-bound system utilizing a molecular docking approach. We find a significant effect of the drug in one case, where the actual mechanism of the reaction is altered from the wild type by mutation. The drug restores both the rate of hydrolysis to the wildtype level and the mechanism of the reaction. This is a way to check the effect of the drug on untested mutations.
摘要：
肥厚型心肌病是遗传性心肌病的最常见形式之一。Mavacamten是一流的肌球蛋白调节剂，通过野生型的活性筛选鉴定，FDA批准用于治疗梗阻性肥厚型心肌病（HCM）。该药物选择性结合心脏β-肌球蛋白，抑制肌球蛋白功能以降低心脏收缩力。尽管该药物被认为会影响肌球蛋白跨桥循环的多个步骤，其详细作用机制仍在调查中。必须查询整个跨桥循环中的各个步骤，以阐明作用的全部机制。在这项研究中,我们利用过渡路径采样的罕见事件方法来生成反应轨迹,以深入了解药物对人心脏β-肌球蛋白ATP水解步骤的动力学和速率的作用.我们研究了三种已知的HCM致病肌球蛋白突变：R453C，P710R,和R712L观察药物对化学步骤中这些突变引起的改变的影响。由于在这项工作时没有药物结合的肌球蛋白的晶体结构，我们利用分子对接方法创建了药物结合系统模型.我们在一个案例中发现了这种药物的显着效果，其中反应的实际机制通过突变从野生型改变。药物将水解速率恢复到野生型水平和反应机理。这是一种检查药物对未经测试的突变的影响的方法。
