Computational biophysical characterization of the SARS-CoV-2 spike protein binding with the ACE2 receptor and implications for infectivity
SARS-CoV-2 is a novel highly virulent pathogen which gains entry to human cells by binding with the cell surface receptor – angiotensin converting enzyme (ACE2). We computationally contrasted the binding interactions between human ACE2 and coronavirus spike protein receptor binding domain (RBD) of the 2002 epidemic-causing SARS-CoV-1, SARS-CoV-2, and bat coronavirus RaTG13 using the Rosetta energy function. We find that the RBD of the spike protein of SARS-CoV-2 is highly optimized to achieve very strong binding with human ACE2 (hACE2) which is consistent with its enhanced infectivity. SARSCoV-2 forms the most stable complex with hACE2 compared to SARS-CoV-1 (23% less stable) or RaTG13 (11% less stable). Notably, we calculate that the SARS-CoV-2 RBD lowers the binding strength of angiotensin 2 receptor type I (ATR1) which is the native binding partner of ACE2 by 44.2%. Strong binding is mediated through strong electrostatic attachments with every fourth residue on the N-terminus alphahelix (starting from Ser19 to Asn53) as the turn of the helix makes these residues solvent accessible. By contrasting the spike protein SARS-CoV-2 Rosetta binding energy with ACE2 of different livestock and pet species we find strongest binding with bat ACE2 followed by human, feline, equine, canine and finally chicken. This is consistent with the hypothesis that bats are the viral origin and reservoir species. These results offer a computational explanation for the increased infection susceptibility by SARSCoV-2 and allude to therapeutic modalities by identifying and rank-ordering the ACE2 residues involved in binding with the virus.
- Research Organization:
- Stanford Univ., CA (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- Grant/Contract Number:
- AC05-00OR22725
- OSTI ID:
- 1762536
- Alternate ID(s):
- OSTI ID: 1816231
- Journal Information:
- Computational and Structural Biotechnology Journal, Journal Name: Computational and Structural Biotechnology Journal Vol. 18 Journal Issue: C; ISSN 2001-0370
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- Sweden
- Language:
- English
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