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. 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 angiotensin 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 coronavirus. 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 electrostatic 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.
【저자키워드】 SARS-CoV-2, molecular dynamics, protein–protein interaction, relative free energy of binding, 【초록키워드】 COVID-19, coronavirus disease, ACE2, coronavirus, Mutation, antibody, SARS-CoV, Diagnosis, Receptor binding domain, 2019 novel coronavirus, Epidemic, Surveillance, outbreak, trajectory, Neutralizing, SARS Coronavirus, binding, Protein–protein interaction, Receptor binding, Contact, similarity, acute respiratory syndrome, Nature, enzyme, host receptor, receptor protein, complex, residue, sequence, help, proline, homology, hydrophobic, contagious, transmission rate, Lancet, enhanced, Effect, FIVE, NAT, Salt Bridge, greater, responsible, carried, contribute, cause, reveal, 80R, electrostatic, polar, hydrophobic packing, nonspecific, Significance, the SARS-CoV-2, 【제목키워드】 Receptor binding, enhanced, hydrophobic interaction,