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Abstract

Molecular dynamics and free energy simulations have been carried out to elucidate the structural origin of differential protein-protein interactions between the common receptor protein angio-tensin converting enzyme 2 (ACE2) and the receptor binding domains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [A. E. Gorbalenya et al., Nat. Microbiol. 5, 536-544 (2020)] that causes coronavirus disease 2019 (COVID-19) [P. Zhou et al., Nature 579, 270-273 (2020)] and the SARS coronavirus in the 2002-2003 (SARS-CoV) [T. Kuiken et al., Lancet 362, 263-270 (2003)] outbreak. Analysis of the dynamic trajectories reveals that the binding interface consists of a primarily hydrophobic region and a delicate hydrogen-bonding network in the 2019 novel coro-navirus. A key mutation from a hydrophobic residue in the SARS-CoV sequence to Lys417 in SARS-CoV-2 creates a salt bridge across the central hydrophobic contact region, which along with polar residue mutations results in greater electrostatic complementarity than that of the SARS-CoV complex. Furthermore, both electro-static effects and enhanced hydrophobic packing due to removal of four out of five proline residues in a short 12-residue loop lead to conformation shift toward a more tilted binding groove in the complex in comparison with the SARS-CoV complex. On the other hand, hydrophobic contacts in the complex of the SARS-CoV-neutralizing antibody 80R are disrupted in the SARS-CoV-2 homology complex model, which is attributed to failure of recognition of SARS-CoV-2 by 80R. protein-protein interaction | SARS-CoV-2 | relative free energy of binding | molecular dynamics T he novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the current outbreak of corona-virus disease 2019 (COVID-19) shares many similarities with the SARS coronavirus in 2002-2003 (SARS-CoV), including 76% sequence identity in the spike protein (S) (1-3), a common receptor of the angiotensin converting enzyme 2 (ACE2) (4-6), and the fusion mechanism that involves cleavages of spike at the S1-S2 and S2ʹ sites (7). Amino acid mutations critical to protein-protein interactions have been identified to play a critical role in human-to-human as well as cross-species transmissions (8, 9). Furthermore, it has been reported that the affinity constant for the receptor binding domain (RBD) of SARS-CoV-2 to ACE2 is greater than that of SARS-CoV by as much as a factor of 10 to 15 (10, 11), and the furin recognition sequence "RRAR" at the S1-S2 cleaving site of SARS-CoV-2 represents a near-optimal match for the cellular serine protease TMPRSS2 (5, 12, 13). Both factors likely contribute to the efficiency of virus transmission, making COVID-19 more contagious than infections by SARS-CoV and the influenza virus. Curiously, a SARS-CoV neutralizing antibody, 80R, that recognizes the S protein with nanomolar affinity (14) in the same interfacial region of ACE2 does not show detectable binding to the RBD of SARS-CoV-2 (11, 15). What mutations in the 2019 novel coronavirus make it a stronger binder to ACE2 than SARS-CoV, but, at the same time, capable of evading the antibody against SARS-CoV? An understanding of the underlying mechanisms for protein-protein association between the ACE2 receptor and the RBD of SARS-CoV-2 as well as the difference from that of SARS-CoV is important for virus detection, epidemic surveillance and prevention, and vaccine and inhibitor design. In this study, we present findings from molecular dynamics (MD) simulations of binary complexes of the RBD domains of both the SARS and COVID-19 viruses with the common receptor ACE2 and the antibody 80R. The present simulations reveal that both electrostatic complementarity and hydrophobic interactions are critical to enhancing receptor binding and escaping antibody recognition by the RBD of SARS-CoV-2. Results Electrostatic Complementarity Is Enhanced in the RBD-ACE2 Complex of SARS-CoV-2. The amino acid sequence of the RBD of SARS-CoV-2 (residue numbers 335 to 515) is highly homologous to that of the SARS-CoV with a single amino acid insertion (Val483) at the edge of the binding interface. Throughout this paper, we use the SARS-CoV-2 sequence number in the discussion and point out the corresponding number for SARS-CoV using a subscript "s." RBD is structurally divided into a core region, consisting of five anti-parallel strands of β-sheet, which is relatively conserved (87.4% sequence identity), and a more variable (50% homology) receptor binding motif (RBM) (SI Appendix, Fig. S1). Sequence variations mainly aggregate in the loop regions, two of which are located at both ends of the dimer contact region, denoted as CR1 and CR3 Significance Enhanced receptor binding by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to contribute to the highly contagious transmission rate of coronavirus disease 2019. An understanding of the structural and energetic details responsible for protein-protein interactions between the host receptor ACE2 and SARS-CoV-2 can be useful to epidemic surveillance, diagnosis, and optimization of neutralizing agents. The present study unravels a delicate balance of specific and nonspecific hydrogen-bonding and hydrophobic networks to help elucidate the similarities and differences in receptor binding by SARS-CoV-2 and SARS-CoV.