Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions

Yingjie Wang

Meiyi Liu

Jiali Gao

^{Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518055, China;}

^{College of Chemical Biology and Biotechnology, Beijing University Shenzhen Graduate School, Shenzhen 518055, China;}

^{Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455;}

^{Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455}

^{To whom correspondence may be addressed. Email:}gro.oagilaij@oag.

Edited by Peter J. Rossky, Rice University, Houston, TX, and approved May 27, 2020 (received for review April 27, 2020)

Author contributions: Y.W. and J.G. designed research; Y.W. and M.L. performed research; Y.W., M.L., and J.G. analyzed data; Y.W., M.L., and J.G. wrote the paper; Y.W. and J.G. initiated the research; and Y.W. and M.L. conducted the computations.

Edited by Peter J. Rossky, Rice University, Houston, TX, and approved May 27, 2020 (received for review April 27, 2020)

This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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.

Keywords: protein–protein interaction, SARS-CoV-2, relative free energy of binding, molecular dynamics

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 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.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the current outbreak of coronavirus 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.

Acknowledgments

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.

Footnotes

The authors declare no competing interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2008209117/-/DCSupplemental.

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Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions

Significance

Abstract

Supplementary File

Supplementary File

Supplementary File

Acknowledgments

Footnotes

References