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

09 November 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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 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.

Keywords

fragment molecular orbital method (FMO)
intermolecular interaction
inter-fragment interaction energy (IFIE)
protein-protein interaction (PPI)
SARS-CoV-2
coronavirus disease 2019 (COVID-19)
spike protein
Angiotensin-converting enzyme 2(ACE2)
antibody
drug design

Supplementary materials

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20201106 spike ace2 b38-fab si v1-fin
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Supplementary weblinks

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