Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland 20742, United States.
Laboratory of Computational Biology, National, Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20824, United States.
J Phys Chem B. 2020 Nov 12;124(45):10034-10047. doi: 10.1021/acs.jpcb.0c05994. Epub 2020 Oct 28.
The novel coronavirus (nCOV-2019) outbreak has put the world on edge, causing millions of cases and hundreds of thousands of deaths all around the world, as of June 2020, let alone the societal and economic impacts of the crisis. The spike protein of nCOV-2019 resides on the virion's surface mediating coronavirus entry into host cells by binding its receptor binding domain (RBD) to the host cell surface receptor protein, angiotensin converter enzyme (ACE2). Our goal is to provide a detailed structural mechanism of how nCOV-2019 recognizes and establishes contacts with ACE2 and its difference with an earlier severe acute respiratory syndrome coronavirus (SARS-COV) in 2002 via extensive molecular dynamics (MD) simulations. Numerous mutations have been identified in the RBD of nCOV-2019 strains isolated from humans in different parts of the world. In this study, we investigated the effect of these mutations as well as other Ala-scanning mutations on the stability of the RBD/ACE2 complex. It is found that most of the naturally occurring mutations to the RBD either slightly strengthen or have the same binding affinity to ACE2 as the wild-type nCOV-2019. This means that the virus had sufficient binding affinity to its receptor at the beginning of the crisis. This also has implications for any vaccine design endeavors since these mutations could act as antibody escape mutants. Furthermore, in silico Ala-scanning and long-timescale MD simulations highlight the crucial role of the residues at the interface of RBD and ACE2 that may be used as potential pharmacophores for any drug development endeavors. From an evolutional perspective, this study also identifies how the virus has evolved from its predecessor SARS-COV and how it could further evolve to become even more infectious.
新型冠状病毒（nCOV-2019）的爆发使全球陷入紧张状态，截至 2020 年 6 月，造成了数百万人感染和数十万人死亡，更不用说这场危机对社会和经济造成的影响了。nCOV-2019 的刺突蛋白位于病毒粒子的表面，通过其受体结合结构域（RBD）与宿主细胞表面受体蛋白血管紧张素转化酶（ACE2）结合，介导冠状病毒进入宿主细胞。我们的目标是通过广泛的分子动力学（MD）模拟，提供关于 nCOV-2019 如何识别和与 ACE2 建立联系的详细结构机制，以及它与 2002 年早些时候的严重急性呼吸系统综合征冠状病毒（SARS-COV）的区别。在世界不同地区从人类中分离出的 nCOV-2019 株中，已经鉴定出 RBD 中的许多突变。在这项研究中，我们研究了这些突变以及其他 Ala 扫描突变对 RBD/ACE2 复合物稳定性的影响。结果发现，RBD 中的大多数自然发生的突变要么略微增强，要么与野生型 nCOV-2019 对 ACE2 的结合亲和力相同。这意味着病毒在危机开始时就具有足够的与受体结合的亲和力。这也对任何疫苗设计工作具有重要意义，因为这些突变可能成为抗体逃逸突变体。此外，基于计算机的 Ala 扫描和长时间尺度的 MD 模拟突出了 RBD 和 ACE2 界面残基的关键作用，这些残基可能被用作任何药物开发工作的潜在药效团。从进化的角度来看，这项研究还确定了病毒如何从其前身 SARS-COV 进化而来，以及它如何进一步进化以变得更具传染性。
