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Issue 13, 2021
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Molecular recognition of SARS-CoV-2 spike glycoprotein: quantum chemical hot spot and epitope analyses

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Abstract

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 interfaces carefully, we identified amino acid residues critical for molecular recognition between S-protein and ACE2 or B38 Fab antibody. Importantly, hydrophobic residues that are involved in weak interactions such as CH–O hydrogen bond 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 antibody design, evaluation of the binding property of the SARS-CoV-2 variants including its N501Y, and small or medium drug design against the SARS-CoV-2.

Graphical abstract: Molecular recognition of SARS-CoV-2 spike glycoprotein: quantum chemical hot spot and epitope analyses

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Supplementary files

Article information


Submitted
27 Nov 2020
Accepted
21 Feb 2021
First published
02 Mar 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021,12, 4722-4739
Article type
Edge Article

Molecular recognition of SARS-CoV-2 spike glycoprotein: quantum chemical hot spot and epitope analyses

C. Watanabe, Y. Okiyama, S. Tanaka, K. Fukuzawa and T. Honma, Chem. Sci., 2021, 12, 4722
DOI: 10.1039/D0SC06528E

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