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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.

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