Molecular recognition of SARS-CoV-2 spike glycoprotein: quantum chemical hot spot and epitope analyses† † Electronic supplementary information (ESI) available: Table S1: IFIE and geometric IFP of XH–Y hydrogen bonds between SARS-CoV-2 S-protein and ACE2. Table S2: IFIE and geometric IFP of XH/π interactions between SARS-CoV-2 S-protein and ACE2. Table S3: IFIE and geometric IFP of XH–Y hydrogen bonds between SARS-CoV-2 S-protein and B38 Fab antibody. Table S4: IFIE and geometric IFP of XH/π interactions between SARS-CoV-2 S-protein and B38 Fab antibody. Table S5: Predicted binding energies between the S-protein and ACE2/B38 Fab antibody without the IFIEs of sugar chain fragments. Table S6: Predicted binding energies (kcal mol−1) between SARS-CoV-2 S-protein WT or N501Y variant and ACE2. Fig. S1: Structural differences on the binding interface of S-protein and ACE2. Fig. S2: Intermolecular interaction energies between SARS-CoV-2 chimeric S-protein and ACE2 in host cells. Fig. S3: Interm

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. Quantum chemical calculations investigated molecular recognition of SARS-CoV-2 spike glycoproteins including its N501Y variant for ACE2 and antibody. Hot spot and epitope analyses revealed key residues to design drugs and antibodies against COVID-19.