Effect of Delta and Omicron Mutations on the RBD-SD1 Domain of the Spike Protein in SARS-CoV-2 and the Omicron Mutations on RBD-ACE2 Interface Complex

Abstract

The receptor-binding domain (RBD) is the essential part in the Spike-protein (S-protein) of SARS-CoV-2 virus that directly binds to the human ACE2 receptor, making it a key target for many vaccines and therapies. Therefore, any mutations at this domain could affect the efficacy of these treatments as well as the viral-cell entry mechanism. We introduce ab initio DFT-based computational study that mainly focuses on two parts: (1) Mutations effects of both Delta and Omicron variants in the RBD-SD1 domain. (2) Impact of Omicron RBD mutations on the structure and properties of the RBD-ACE2 interface system. The in-depth analysis is based on the novel concept of amino acid-amino acid bond pair units (AABPU) that reveal the differences between the Delta and/or Omicron mutations and its corresponding wild-type strain in terms of the role played by non-local amino acid interactions, their 3D shapes and sizes, as well as contribution to hydrogen bonding and partial charge distributions. Our results also show that the interaction of Omicron RBD with ACE2 significantly increased its bonding between amino acids at the interface providing information on the implications of penetration of S-protein into ACE2, and thus offering a possible explanation for its high infectivity. Our findings enable us to present, in more conspicuous atomic level detail, the effect of specific mutations that may help in predicting and/or mitigating the next variant of concern.

Comparative Surface Electrostatics and Normal Mode Analysis of High and Low Pathogenic H7N7 Avian Influenza Viruses

“…Recently, the infectivity and immune escape of another pandemic virus, SARS-CoV-2, were also found to be influenced by variation in surface electrostatics of the spike protein, as reported by comparative analysis of the SARS-CoV-2 variants [ 47 , 48 , 49 ].Lessons from comparative studies on hemagglutinin and spike protein features suggest that variation in surface electrostatics of the capsid proteins that mediate binding to the host cell functional receptors is a driving force and a functional fingerprint in the evolution of pandemic viruses.…”

Three Amino Acid Substitutions in the Spike Protein Enable the Coronavirus Porcine Epidemic Diarrhea Virus To Infect Vero Cells

“…On the one side, the mutations at positions 891 and 893 abolished the original trypsin cleavage site and at the same time exposed an alternative site to another protease that assists the virus in entering the cells through endocytosis ( 26 , 27 ). On the other side, the DR13 att strain could have found a new receptor on Vero cells or a new way to interact with the receptor, as could be inferred from the mutations at positions 605 and 633, which may cause an alteration in the three-dimensional (3D) structure of the RBD and a change in the dynamic process of ligand-receptor interactions ( 23 , 28 ). No doubt, it was the culture conditions of the virus that dominated such a selection, as inconsistent trypsin activity during passaging but the stable physical chemistry environment of the culture system made the selection of an adapted virus possible.…”

Changes in total charge on spike protein of SARS-CoV-2 in emerging lineages

“…resort to simulations based on density functional theory Ching et al, 2023), which can be computationally prohibitive even for a single S protein structure, let alone for such a large dataset.…”