Molecular Insights into the Differential Dynamics of SARS-CoV-2 Variants of Concern (VOC)

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected the lives and livelihood of millions of individuals around the world. It has mutated several times after its first inception, with an estimated two mutations occurring every month. Although we have been successful in developing vaccines against the virus, emergence of variants has enabled it to escape therapy. Few of the generated variants are also reported to be more infectious than the Wild-type. The World Health Organization (WHO) has prioritized the variants into Variants of Concern (VOC) and Variants of Interest (VOI) to focus on the variants that pose a threat to public health. In this study, we compare the structural and dynamic attributes of all the RBD/ACE2 complexes for the reported VOCs, namely, Alpha, Beta, Gamma, and Delta through atomistic simulations. Results indicated that the orientation and binding energies of the VOCs were different from the Wild-type. Specifically, we observed that the Receptor Binding Domain (RBD) in B.1.351 (Beta) and B.1.617.2 (Delta) underwent a relative rotation to make the complex more compact. Protein dynamics, however, show that their fluctuations were similar to the Wild-type. It was also reflected in the calculation of the total interaction energies. Overall, it was observed that electrostatic interactions play a major role in the formation of the complexes. Detailed residue level energetics revealed that the most prominent changes in interaction energies were seen particularly at the mutated residues which were present at RBD/ACE2 interface. We found that B.1.167.2 (Delta) is one of the most tightly bound variants of SARS-CoV-2 with dynamics similar to Wild-type. High binding affinity of RBD towards ACE2 is indicative of an increase in the viral infectivity. Therefore, the intrinsic details presented in this study would be useful for the design and development of effective therapeutic strategies for the emerging variants of the virus.

Scanning the RBD-ACE2 molecular interactions in Omicron variant

“…Detailed RMS fluctuations of the Cα atoms of the residues shows some interesting observations. Compared with earlier studies with Alpha, Beta, Gamma and Delta 13 , the RMSF values of the Omicron variant over the simulation time were lower than the Wild-type (Figure 1b, c). This is noteworthy since earlier mutational studies had shown the RMSF values to be either similar or higher than the Wild-type system.…”

“…Since the primary role of RBD lies in the binding with the ACE2 receptor, the identified mutations would also influence the nature of interaction in the protein-protein complex as observed in earlier studies 11 . Molecular studies have shown that mutations have resulted in variation in the residue wise interaction energies reported for SARS and SARS-CoV-2 as well as in other variants 12,13 .…”

Comparative Structural Analysis of Human ACE2 Receptor with Spike Protein of SARS-CoV-2 Variants: Implications to Understand Infectivity of the Virus

“…There have been few other recent studies such as ours that have explained the binding interactions of RBD of spike protein to ACE2 receptor. 25 , 26 In comparison to these, our study has the following advantages: (1) binding studies of RBD from α, β, γ, δ and the most recent omicron variants to human ACE2 receptor have been delineated; (2) binding parameters have been correlated to the infectivity of each of the five strains; (3) intermolecular interactions between RBD and ACE2 receptor have been highlighted in detail, and (4) holistic approach of understanding the effect of mutations at level of sequence, secondary structural motifs and three-dimensional fold has been adopted.…”