Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

Abstract

The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID‐19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike–angiotensin‐converting enzyme‐2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse‐grained model. Our study extended beyond the receptor‐binding domain (RBD) of spike trimer through comprehensive modeling of the full‐length spike trimer rather than just the RBD. Our free‐energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full‐length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.

The Diverse Nature of the Molecular Interactions That Govern the COV-2 Variants’ Cell Receptor Affinity Ranking and Its Experimental Variability

“…There has been an intensive effort aimed at understanding the spike–cell receptor and spike–antibody interactions using computational chemistry and especially molecular mechanics/molecular dynamics (MM/MD) tools [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. The study of protein associations by MM/MD calculations represents a grand challenge in computational biochemistry since they involve the study of protein–protein interactions (PPIs), a difficult task given the size of the systems involved and the fact that protein–protein interactions (like antibody–antigen) are mediated by residue residents in loops, the most flexible secondary structure [ 27 , 28 ].…”

“…Most previous work aiming at ranking the spike–receptor affinities of the VOCs studied in this work resulted in the following order (see, for instance, refs. [ 20 , 21 , 24 ]).…”