Key Interacting Residues between RBD of SARS-CoV-2 and ACE2 Receptor: Combination of Molecular Dynamics Simulation and Density Functional Calculation
Key Interacting Residues between RBD of SARS-CoV-2 and ACE2 Receptor: Combination of Molecular Dynamics Simulation and Density Functional Calculation
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DOI：
10.1021/acs.jcim.1c00560
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发表时间：
2021-08-24
影响因子：
5.6
通讯作者：
Ching, Wai-Yim
中科院分区：
文献类型：
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作者：
Jawad, Bahaa;Adhikari, Puja;Ching, Wai-Yim
SARS-CoV-2的刺突蛋白通过其受体结合结构域（RBD）与ACE2受体结合，RBD-ACE2复合物是疫苗开发的重要分子靶点，可以阻止病毒感染的增殖。系统地进行了分子、氨基酸和原子水平的计算分析，以确定SARS-CoV和SARS-CoV-2及其α和β变体的RBD-ACE2复合物形成过程中的关键相互作用AA。本研究采用分子动力学（MD）模拟和分子力学广义Born表面积（MM-GBSA）方法来预测结合自由能（BFE）和确定实际相互作用原子，以及基于密度泛函理论（DFT）实现的两种从头算量子化学方案。基于MD结果，确定Q（493）、Y-505、Q（498）、N-501、T-500、N-487、Y-449、F-486、K-417、Y-489、F-456、Y-495和L-455为SARS-CoV-2 RBD热点，ACE2热点为K-353、K-31、D-30、D-355、H-34、D-38、Q（24）、T-27、Y-83、Y-41和E-35。由于N501Y突变，α和β变异的RBD的相互作用aa略有不同。静电和疏水相互作用是形成AA-AA结合对的主要驱动力。我们证实RBD中的Q（493）、Q（498）、N-501、F-486、K-417和F-456是与SARS-CoV相比，SARS-CoV-2与ACE2紧密结合的关键残基。带有α变体的RBD与ACE2的结合比野生型RBD或β型RBD强。在Beta变体中，K417N降低了结合，E484K略微增强了结合，N501Y与Alpha一样显著增加了结合。DFT结果表明，SARS2 RBD中的N-487、Q（493）、Y-449、T-500、G（496）、G（446）和G（502）通过与ACE2中的Q（24）、H-34、E-35、D-38、Y-41、Q（42）和K-353形成氢键对。
The spike protein of SARS-CoV-2 binds to the ACE2 receptor via its receptor-binding domain (RBD), with the RBD-ACE2 complex presenting an essential molecular target for vaccine development to stall the virus infection proliferation. The computational analyses at molecular, amino acid (AA), and atomic levels have been performed systematically to identify the key interacting AAs in the formation of the RBD-ACE2 complex for SARS-CoV and SARS-CoV-2 with its Alpha and Beta variants. Our study uses the molecular dynamics (MD) simulations with the molecular mechanics generalized Born surface area (MM-GBSA) method to predict the binding free energy (BFE) and to determine the actual interacting AAs, as well as two ab initio quantum chemical protocols based on the density functional theory (DFT) implementation. Based on MD results, Q(493), Y-505, Q(498), N-501, T-500, N-487, Y-449, F-486, K-417, Y-489, F-456, Y-495, and L-455 have been identified as hotspots in SARS-CoV-2 RBD, while those in ACE2 are K-353, K-31, D-30, D-355, H-34, D-38, Q(24), T-27, Y-83, Y-41, and E-35. RBD with Alpha and Beta variants has slightly different interacting AAs due to N501Y mutation. Both the electrostatic and hydrophobic interactions are the main driving force to form the AA-AA binding pairs. We confirm that Q(493), Q(498), N-501, F-486, K-417, and F-456 in RBD are the key residues responsible for the tight binding of SARS-CoV-2 with ACE2 compared to SARS-CoV. RBD with the Alpha variant binds with ACE2 stronger than the wild-type RBD or Beta. In the Beta variant, K417N reduces the binding, E484K slightly enhances it, and N501Y significantly increases it as in Alpha. The DFT results reveal that N-487, Q(493), Y-449, T-500, G(496), G(446), and G(502) in RBD of SARS2 form pairs via specific hydrogen bonding with Q(24), H-34, E-35, D-38, Y-41, Q(42), and K-353 in ACE2.