Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721, United States.
Department of Biomedical Engineering, University of Arizona, Tucson, Arizona 85724, United States.
J Phys Chem B. 2024 May 16;128(19):4716-4727. doi: 10.1021/acs.jpcb.4c01601. Epub 2024 May 6.
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.
肥厚型心肌病是最常见的遗传性心肌病之一。Mavacamten 是一种首创的肌球蛋白调节剂，是通过对野生型的活性筛选发现的，已获得 FDA 批准用于治疗梗阻性肥厚型心肌病（HCM）。该药物选择性地与心脏β-肌球蛋白结合，抑制肌球蛋白的功能，从而降低心肌收缩力。尽管该药物被认为会影响肌球蛋白横桥循环的多个步骤，但它的详细作用机制仍在研究中。必须查询整个横桥循环的各个步骤，以阐明其完整的作用机制。在这项研究中，我们利用罕见事件方法过渡路径采样来生成反应轨迹，以深入了解药物对人心脏β-肌球蛋白的 ATP 水解步骤动力学和速率的作用。我们研究了三种已知的肥厚型心肌病致病肌球蛋白突变：R453C、P710R 和 R712L，以观察药物对化学步骤中这些突变引起的变化的影响。由于在进行这项工作时没有药物结合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的模型。我们发现药物在一种情况下有显著的效果，其中反应的实际机制因突变而与野生型不同。药物将水解的速率恢复到野生型水平，并恢复反应的机制。这是一种检查药物对未经测试的突变影响的方法。
