Theoretical and Computational Chemistry

Key Interacting Residues Between RBD of SARS-CoV-2 and ACE2 Receptor: Combination of Molecular Dynamic Simulation and Density Functional Calculation

Wai-Yim Ching University of Missouri-Kansas City


The spike protein of SARS-CoV-2 binds to 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 analysis 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, including the MD simulations with molecular mechanics generalized Born surface area (MM-GBSA) method to predict 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, Q493, Y505, Q498, N501, T500, N487, Y449, F486, K417, Y489, F456, Y495, and L455 have been identified as hotspots in RBD, while those in ACE2 are K353, K31, D30, D355, H34, D38, Q24, T27, Y83, Y41, E35, and E37. Both the electrostatic and hydrophobic interactions are the main driving force to form the AA-AA binding pairs. We confirm that Q493, N501, F486, K417, and F456 in RBD are the key residues responsible for the tight binding of SARS-CoV-2 with ACE2 compared to SARS-CoV. The DFT results reveal that N487, Q493, Y449, T500, G496, G446 and G502 in RBD form pairs via specific hydrogen bonding with Q24, H34, E35, D38, Y41, Q42 and K353 in ACE2.

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