Omicron (B.1.1.529) has emerged as the latest SARS-CoV-2 variant of concern (VOC) that features enhanced transmissibility and immune escape. Omicron carries upwards of 50 mutations in its genome, 30 of which exist in the gene encoding the S protein. Strikingly, 15 of those mutations occurred in the Omicron receptor-binding domain (RBD) that binds with the human angiotensin-converting enzyme 2 (ACE2) receptor. Since S protein’s binding to the human ACE2 receptor is the initial key step for host cell entry, it is necessary to assess the effects of Omicron VOC mutations on the S affinity for the ACE2 receptor. Here, we have carried out a comparative analysis of the molecular recognition of the RBDs of the wild type (WT) and Omicron by the human ACE2 based on x-ray crystal structures of their respective complexes. First, we systematically examined the binding pocket of both crystal structures to identify all non-bonded intermolecular interactions that are responsible for S protein’s molecular recognition by ACE2. Subsequently, the strengths of interaction energies between all interface residues in WT and Omicron and their interacting residues in ACE2 were quantified by means of the supermolecular approach using quantum mechanics method at the B2PLYP level. It was found that Omicron binds to ACE2 with higher affinity. Several hot spot residues from the mutated S protein are identified as the molecular determinants for the enhanced binding. The intermolecular interaction energy of mutated residues N477, R493, R498 and Y501 with ACE2 are -1.8, -6.3, -8.2 and -8.3 kcal/mol, respectively. In contrast, the intermolecular interaction energy for the corresponding WT residues S477, Q493, Q498 and N501 are -0.02, -0.4, -3.1 and -4.1 kcal/mol, respectively. This increase in binding affinity is ascribed to new hydrogen bond formed by N477, salt bridge formed by R493, salt bridge, cation-π and CH-π interactions formed by R498, and π-π and CH-π interactions formed by Y501. This quantification of binding affinity enhancement for Omicron, at an advanced level of electronic structure calculation, provides a molecular level explanation for the observed rapid transmission of the Omicron VOC. Moreover, the unravelling of molecular determinants for binding of the highly infectious SARS-CoV-2 Omicron variant to the human ACE2 receptor may be valuable in future for the development of targeted therapies against current and future variants of Covid-19.

Molecular determinants for binding of the highly infectious SARS-CoV-2 Omicron variant to the human ACE2 receptor — A quantum chemical analysis

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