Machine Learning Reveals the Critical Interactions for SARS-CoV-2 Spike Protein Binding to ACE2

Pavlova, Anna; Zhang, Zijian; Acharya, Atanu; Lynch, Diane L.; Pang, Yui Tik; Mou, Zhongyu; Parks, Jerry M.; Chipot, Chris; Gumbart, James C.

doi:10.1021/acs.jpclett.1c01494

Machine Learning Reveals the Critical Interactions for SARS-CoV-2 Spike Protein Binding to ACE2

Journal Article · Fri Jun 04 00:00:00 EDT 2021 · Journal of Physical Chemistry Letters

DOI:https://doi.org/10.1021/acs.jpclett.1c01494· OSTI ID:1814254

Pavlova, Anna ^[1]; Zhang, Zijian ^[1]; ^[1]; Lynch, Diane L. ^[1]; Pang, Yui Tik ^[1]; ^[2]; ^[2]; ^[3]; ^[1]

Georgia Inst. of Technology, Atlanta, GA (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Centre National de la Recherche Scientifique (CNRS), Vandoeuvre-les-Nancy (France); Univ. of Illinois at Urbana-Champaign, IL (United States)

SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Herein, we have used molecular dynamics (MD) simulations, machine learning (ML), and free-energy perturbation (FEP) calculations to elucidate the differences in binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD–ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1814254

Journal Information:: Journal of Physical Chemistry Letters, Journal Name: Journal of Physical Chemistry Letters Journal Issue: 23 Vol. 12; ISSN 1948-7185

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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