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 SARSCoV 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 SARSCoV- 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.
|Original language||English (US)|
|Number of pages||8|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Jun 23 2020|
Bibliographical noteFunding Information:
This research has been supported in part by Shenzhen Municipal Science and Technology Innovation Commission (KQTD2017- 0330155106581) and the National Natural Science Foundation of China (21533003) for work performed at the Shenzhen Bay Laboratory Computing Center and the National Institutes of Health (GM46736) for additional analysis in Minnesota.
ACKNOWLEDGMENTS. This research has been supported in part by Shenz-hen Municipal Science and Technology Innovation Commission (KQTD2017-0330155106581) and the National Natural Science Foundation of China (21533003) for work performed at the Shenzhen Bay Laboratory Computing Center and the National Institutes of Health (GM46736) for additional analysis in Minnesota.
- Molecular dynamics
- Protein-protein interaction
- Relative free energy of binding