Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.
National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.
Proteins. 2021 Sep;89(9):1134-1144. doi: 10.1002/prot.26086. Epub 2021 Apr 26.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2's higher infectivity lies partly in its host receptor recognition mechanism. Experiments show that the human angiotensin converting enzyme 2 (ACE2) protein, which serves as the primary receptor for both CoVs, binds to the receptor binding domain (RBD) of CoV-2's spike protein stronger than SARS-CoV's spike RBD. The molecular basis for this difference in binding affinity, however, remains unexplained from X-ray structures. To go beyond insights gained from X-ray structures and investigate the role of thermal fluctuations in structure, we employ all-atom molecular dynamics simulations. Microseconds-long simulations reveal that while CoV and CoV-2 spike-ACE2 interfaces have similar conformational binding modes, CoV-2 spike interacts with ACE2 via a larger combinatorics of polar contacts, and on average, makes 45% more polar contacts. Correlation analysis and thermodynamic calculations indicate that these differences in the density and dynamics of polar contacts arise from differences in spatial arrangements of interfacial residues, and dynamical coupling between interfacial and non-interfacial residues. These results recommend that ongoing efforts to design spike-ACE2 peptide blockers will benefit from incorporating dynamical information as well as allosteric coupling effects.
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 造成的感染、死亡和经济破坏比 2002-2003 年的严重急性呼吸综合征冠状病毒 (SARS-CoV) 要多得多。了解 SARS-CoV-2 更高传染性的关键部分在于其宿主受体识别机制。实验表明，血管紧张素转换酶 2 (ACE2) 蛋白作为两种冠状病毒的主要受体，与 CoV-2 的刺突蛋白的受体结合域 (RBD) 的结合比 SARS-CoV 的刺突 RBD 更强。然而，从 X 射线结构上解释这种结合亲和力差异的分子基础仍然未知。为了超越从 X 射线结构中获得的见解，并研究热波动在结构中的作用，我们采用全原子分子动力学模拟。微秒级的模拟表明，虽然 CoV 和 CoV-2 刺突-ACE2 界面具有相似的构象结合模式，但 CoV-2 刺突通过更大的极性接触组合与 ACE2 相互作用，平均形成 45%更多的极性接触。相关分析和热力学计算表明，这些极性接触密度和动态差异源于界面残基空间排列的差异，以及界面和非界面残基之间的动态耦合。这些结果表明，为设计刺突-ACE2 肽阻滞剂而进行的持续努力将受益于结合动力学信息以及别构偶联效应。
