Hashem Shaima, Tiberti Matteo, Fornili Arianna
School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom.
The Thomas Young Centre for Theory and Simulation of Materials, London, United Kingdom.
PLoS Comput Biol. 2017 Nov 6;13(11):e1005826. doi: 10.1371/journal.pcbi.1005826. eCollection 2017 Nov.
New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations.
骨骼和心肌疾病药物治疗的新的有前景的途径依赖于直接肌节调节剂，即能够直接结合肌节蛋白并抑制或增强其活性的分子。最近的一项突破是发现了肌球蛋白激活剂奥米卡替麦卡比（OM），它已被证明能增加心肌的功率输出，目前正处于治疗心力衰竭的临床试验阶段。虽然OM对肌球蛋白机械化学循环的总体作用是增加肌节中与肌动蛋白紧密结合的肌球蛋白分子比例，但其作用的分子基础仍不完全清楚。我们在此展示了一项结合OM的人心脏肌球蛋白运动结构域的分子动力学研究，首次以原子分辨率研究了药物对蛋白质动力学性质的影响。我们发现OM对肌球蛋白动力学有双重作用，即a）增加转换器和杠杆臂亚结构域与蛋白质其余部分运动的耦合，以及b）重新连接动态关联网络，从而在OM结合位点和远处功能区域之间产生优先通信途径。负责这些作用的残基位置提示了未来开发改进药物以及针对特定心肌病相关突变的可能策略。
