Xie Yixin, Karki Chitra B, Du Dan, Li Haotian, Wang Jun, Sobitan Adebiyi, Teng Shaolei, Tang Qiyi, Li Lin
Computational Science Program, University of Texas at El Paso, El Paso, TX, United States.
Department of Physics, University of Texas at El Paso, El Paso, TX, United States.
Front Mol Biosci. 2020 Dec 9;7:591873. doi: 10.3389/fmolb.2020.591873. eCollection 2020.
The ongoing outbreak of COVID-19 has been a serious threat to human health worldwide. The virus SARS-CoV-2 initiates its infection to the human body via the interaction of its spike (S) protein with the human Angiotensin-Converting Enzyme 2 (ACE2) of the host cells. Therefore, understanding the fundamental mechanisms of how SARS-CoV-2 S protein receptor binding domain (RBD) binds to ACE2 is highly demanded for developing treatments for COVID-19. Here we implemented multi-scale computational approaches to study the binding mechanisms of human ACE2 and S proteins of both SARS-CoV and SARS-CoV-2. Electrostatic features, including electrostatic potential, electric field lines, and electrostatic forces of SARS-CoV and SARS-CoV-2 were calculated and compared in detail. The results demonstrate that SARS-CoV and SARS-CoV-2 S proteins are both attractive to ACE2 by electrostatic forces even at different distances. However, the residues contributing to the electrostatic features are quite different due to the mutations between SARS-CoV S protein and SARS-CoV-2 S protein. Such differences are analyzed comprehensively. Compared to SARS-CoV, the SARS-CoV-2 binds with ACE2 using a more robust strategy: The electric field line related residues are distributed quite differently, which results in a more robust binding strategy of SARS-CoV-2. Also, SARS-CoV-2 has a higher electric field line density than that of SARS-CoV, which indicates stronger interaction between SARS-CoV-2 and ACE2, compared to that of SARS-CoV. Key residues involved in salt bridges and hydrogen bonds are identified in this study, which may help the future drug design against COVID-19.
新型冠状病毒肺炎（COVID-19）的持续爆发对全球人类健康构成了严重威胁。严重急性呼吸综合征冠状病毒2（SARS-CoV-2）通过其刺突（S）蛋白与宿主细胞的人血管紧张素转换酶2（ACE2）相互作用引发对人体的感染。因此，深入了解SARS-CoV-2 S蛋白受体结合域（RBD）与ACE2结合的基本机制对于开发COVID-19治疗方法至关重要。在此，我们采用多尺度计算方法研究了人ACE2与SARS-CoV和SARS-CoV-2的S蛋白的结合机制。详细计算并比较了SARS-CoV和SARS-CoV-2的静电特征，包括静电势、电场线和静电力。结果表明，即使在不同距离下，SARS-CoV和SARS-CoV-2的S蛋白对ACE2均具有静电力吸引力。然而，由于SARS-CoV S蛋白与SARS-CoV-2 S蛋白之间的突变，导致对静电特征有贡献的残基存在很大差异。对这些差异进行了全面分析。与SARS-CoV相比，SARS-CoV-2与ACE2结合采用了更稳健的策略：与电场线相关的残基分布差异很大，这导致SARS-CoV-2的结合策略更稳健。此外，SARS-CoV-2的电场线密度高于SARS-CoV，这表明与SARS-CoV相比，SARS-CoV-2与ACE2之间的相互作用更强。本研究确定了参与盐桥和氢键的关键残基，这可能有助于未来针对COVID-19的药物设计。
