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Molecular Recognition of SARS-CoV-2 Spike Glycoprotein: Quantum Chemical Hot Spot and Epitope Analyses

revised on 26.11.2020, 22:23 and posted on 27.11.2020, 08:04 by Chiduru Watanabe, Yoshio Okiyama, Shigenori Tanaka, Kaori Fukuzawa, Teruki Honma
Due to the COVID-19 pandemic, researchers have attempted to identify complex structures of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S-protein) with angiotensin-converting enzyme 2 (ACE2) or a blocking antibody. However, the molecular recognition mechanism - critical information for drug and antibody design - has not been fully clarified at the amino acid residue level. Elucidating such a microscopic mechanism in detail requires a more accurate molecular interpretation that includes quantum mechanics to quantitatively evaluate hydrogen bonds, XH/π interactions (X = N, O, and C), and salt bridges. In this study, we applied the fragment molecular orbital (FMO) method to characterize the SARS-CoV-2 S-protein binding interactions with not only ACE2 but also the B38 Fab antibody involved in ACE2-inhibitory binding. By analyzing FMO-based interaction energies along a wide range of binding inter-faces carefully, we identified amino acid residues critical for molecular recognition between S-protein and ACE2 or B38 Fab antibody. Importantly, hydrophobic residues that attribute to weak interactions such as CH-O and XH/π interactions, as well as polar residues that construct conspicuous hydrogen bonds, play important roles in molecular recognition and binding ability. Moreover, through these FMO-based analyses, we also clarified novel hot spots and epitopes that had been overlooked in previous studies by structural and molecular mechanical approaches. Altogether, these hot spots/epitopes identified between S-protein and ACE2/B38 Fab antibody may provide useful information for future anti-body design and small or medium drug design against the SARS-CoV-2.


AMED/BINDS (JP20am0101113)



Email Address of Submitting Author


Center for Biosystems Dynamics Research, RIKEN



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest

Version Notes

3nd version, 2020/11/27 JST