The Spike Protein of SARS-CoV-2 Is Adapting Because of Selective Pressures

Abstract

The global scale of the COVID-19 pandemic has demonstrated the evolution of SARS-CoV-2 and the clues of adaptation. After two years and two months since the declaration of the pandemic, several variants have emerged and become fixed in the human population thanks to extrinsic selective pressures but also to the inherent mutational capacity of the virus. Here, we applied a neutral substitution evolution test to the spike (S) protein of Omicron’s protein and compared it to the others’ variant of concern (VOC) neutral evolution. We carried out comparisons among the interactions between the S proteins from the VOCs (Alpha, Beta, Gamma, Delta and Omicron) and the receptor ACE2. The shared amino acids among all the ACE2 binding S proteins remain constant, indicating that these amino acids are essential for the accurate binding to the receptor. The complexes of the RBD for every variant with the receptor were used to identify the amino acids involved in the protein—protein interaction (PPI). The RBD of Omicron establishes 82 contacts, compared to the 74 of the Wuhan original viral protein. Hence, the mean number of contacts per residue is higher, making the contact thermodynamically more stable. The RBDs of the VOCs are similar in sequence and structure; however, Omicron’s RBD presents the largest deviation from the structure by 1.11 Å RMSD, caused by a set of mutations near the glycosylation N343. The chemical properties and structure near the glycosylation N343 of the Omicron S protein are different from the original protein, which provoke reduced recognition by the neutralizing antibodies. Our results hint that selective pressures are induced by mass vaccination throughout the world and by the persistence of recurrent infections in immunosuppressed individuals, who did not eliminate the infection and ended up facilitating the selection of viruses whose characteristics are different from the previous VOCs, less pathogenic but with higher transmissibility.

SARS‐CoV‐2 neutralizing antibody epitopes are overlapping and highly mutated which raises the chances of escape variants and requires development of broadly reactive vaccines

“…However, the recent Omicron variant shows the highest (>30 aa) mutations across the spike protein (Figure 2A,B). The current data in accordance with recent reports suggests that these variants might have co‐evolved with host adaptation and selective immune pressure, raising the chances of having antibody escape variants 7,12,13 …”

“…The decrease in affinity of mAbs towards the spike variants is clearly demonstrated by the increased Kd and IC 50 values of mAbs including the well characterized REGN10933, LY‐CoV555, LY‐CoV016, and REGN10987. Consistant with previous reports, our data suggest that consequences in host adaptation along with other factors including immune pressure might trigger the chances of emergence of antibody escape variants with increased tropism and transmissibility 12,13 …”

“…The current data in accordance with recent reports suggests that these variants might have co-evolved with host adaptation and selective immune pressure, raising the chances of having antibody escape variants. 7,12,13 3.3 | Epitope map of SARS-CoV-2 neutralizing monoclonal antibodies shows conserved overlapping epitope residues majorly localized to receptor binding domain of spike glycoprotein…”

“…The increasing trend of human‐human transmission and accumulation of diverse favorable mutations in the spike protein of SARS‐CoV‐2 lead to the generation of several naturally occurring variants including the Delta and Omicron 7 . Recent reports demonstrate that selective pressures mediated by mass vaccinations as well as adaptation of SARS‐CoV‐2 to mAb treatment might facilitate the emergence of novel variants which are resistant to antibodies and show higher transmission 12,13 . Proper understanding of the conservation of amino acid mutations within the Alpha, Beta, Gamma, Delta, and Omicron variants and changes associated at critical epitope residues of neutralizing monoclonal antibodies delineates the importance of developing novel vaccine candidates or therapeutics targeting current or future SARS‐CoV‐2 variants.…”

“…7 Recent reports demonstrate that selective pressures mediated by mass vaccinations as well as adaptation of SARS-CoV-2 to mAb treatment might facilitate the emergence of novel variants which are resistant to antibodies and show higher transmission. 12,13 Proper understanding of the conservation of amino acid mutations within the Alpha, Beta, Gamma, Delta, and Omicron variants and changes associated at…”