# Electronic Interactions Between the Receptor-Binding Domain of Omicron Variants and Angiotensin-Converting Enzyme 2: A Novel Amino Acid–Amino Acid Bond Pair Concept

## TL;DR

This paper introduces a new method to study how mutations in Omicron variants affect their binding to human cells.

## Contribution

A novel amino acid–amino acid bond pair concept is developed to quantify interactions in the RBD–ACE2 complex.

## Key findings

- Binding between RBD and ACE2 is strongest in Omicron BA.1, followed by BA.2, then the wild type.
- Unmutated sites in the RBD–ACE2 interface are also impacted by mutations in Omicron variants.
- Partial charge values for 311 residues across five models are calculated to understand mutation effects.

## Abstract

SARS-CoV-2 remains a severe threat to worldwide public health, particularly as the virus continues to evolve and diversify into variants of concern (VOCs). Among these VOCs, Omicron variants exhibit unique phenotypic traits, such as immune evasion, transmissibility, and severity, due to numerous spike protein mutations and the rapid subvariant evolution. These Omicron subvariants have more than 15 mutations in the receptor-binding domain (RBD), a region of the SARS-CoV-2 spike protein that is important for recognition and binding with the angiotensin-converting enzyme 2 (ACE2) human receptor. To address the impact of these high numbers of Omicron mutations on the binding process, we have developed a novel method to precisely quantify amino acid interactions via the amino acid–amino acid bond pair (AABP). We applied this concept to investigate the interface interactions of the RBD–ACE2 complex in four Omicron Variants (BA.1, BA.2, BA.5, and XBB.1.16) with its Wild Type counterpart. Based on the AABP analysis, we have identified all the sites that are affected by mutation and have provided evidence that unmutated sites are also impacted by mutation. We have calculated that the binding between RBD and ACE2 is strongest in OV BA.1, followed by OV BA.2, WT, OV BA.5, and OV XBB.1.16. We also present the partial charge values for all 311 residues across these five models. Our analysis provides a detailed understanding of changes caused by mutation in each Omicron interface complex.