Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

Abstract

The initial step of infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) involves the binding of receptor binding domain (RBD) of the spike protein to the angiotensin converting enzyme 2 (ACE2) receptor. Each successive wave of SARS‐CoV‐2 reports emergence of many new variants, which is associated with mutations in the RBD as well as other parts of the spike protein. These mutations are reported to have enhanced affinity towards the ACE2 receptor as well as are also crucial for the virus transmission. Many computational and experimental studies have demonstrated the effect of individual mutation on the RBD‐ACE2 binding. However, the cumulative effect of mutations on the RBD and away from the RBD was not investigated in detail. We report here a comparative analysis on the structural communication and dynamics of the RBD and truncated S1 domain of spike protein in complex with the ACE2 receptor from SARS‐CoV‐2 wild type and its P.1 variant. Our integrative network and dynamics approaches highlighted a subtle conformational changes in the RBD as well as truncated S1 domain of spike protein at the protein contact level, responsible for the increased affinity with the ACE2 receptor. Moreover, our study also identified the commonalities and differences in the dynamics of the interactions between spike protein of SARS‐CoV‐2 wild type and its P.1 variant with the ACE2 receptor. Further, our investigation yielded an understanding towards identification of the unique RBD residues crucial for the interaction with the ACE2 host receptor. Overall, the study provides an insight for designing better therapeutics against the circulating P.1 variants as well as other future variants.

Structural communication fingerprinting and dynamic investigation of RBD-hACE2 complex from BA.1 × AY.4 recombinant variant (Deltacron) of SARS-CoV-2 to decipher the structural basis for enhanced transmission

“…The surface mapping of hub residues on the structure of the wild type hACE2-RBD complex and Deltacron RBD in complex with hACE2 are shown in Figure 3A and 3B. Consistent with the previous results on P.1 variant the mutated residues perturbed the hub residues network and particularly in the RBD of Deltacron complex [37]. The stabilizing anti-parallel beta-sheets in the structure of RBD also demonstrated notable variation in the hub residues.…”

“…It indicate that due to the significant number of mutation in the Deltacron variant the hub residues variations are also significant. For instance, variations in the hubs are also reported in the P.1 variant where decrease in the hub residues in the variant complex was also observed [37]. Hence, it show the structural perturbation caused by these mutations, which consequently used alternate interaction pattern with the host receptor.…”

Effect of computationally designed fragment-based analogs on the RBD–ACE2 complex of the SARS-CoV-2 P.1 variant

“…As reported in our previous study, the interacting interface residues have already been characterized as critical druggable targets. 23…”

“…[20][21][22] The functional significance of the mutations has already been discussed in our previous study, where we have highlighted the changes between the wild-type SARS-CoV-2 (WT) and its P.1 variant at their structural and contact level responsible for the increased affinity towards human ACE2 receptor. 23 This intrigues us to target the RBD-ACE2 complex of the P.1 variant. The P.1 variant consists of three RBD interface mutations (K417T, E484K, and N501Y) and has gained much attention since the variant storms.…”