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With the emergence of Delta and Omicron variants, many other important variants of SARS-CoV-2, which cause Coronavirus disease-2019, including A.30, are reported to increase the concern created by the global pandemic. The A.30 variant, reported in Tanzania and other countries, harbors spike gene mutations that help this strain to bind more robustly and to escape neutralizing antibodies. The present study uses molecular modelling and simulation-based approaches to investigate the key features of this strain that result in greater infectivity. The protein-protein docking results for the spike protein demonstrated that additional interactions, particularly two salt-bridges formed by the mutated residue Lys484, increase binding affinity, while the loss of key residues at the N terminal domain (NTD) result in a change to binding conformation with monoclonal antibodies, thus escaping their neutralizing effects. Moreover, we deeply studied the atomic features of these binding complexes through molecular simulation, which revealed differential dynamics when compared to wild type. Analysis of the binding free energy using MM/GBSA revealed that the total binding free energy (TBE) for the wild type receptor-binding domain (RBD) complex was -58.25 kcal/mol in contrast to the A.30 RBD complex, which reported -65.59 kcal/mol. The higher TBE for the A.30 RBD complex signifies a more robust interaction between A.30 variant RBD with ACE2 than the wild type, allowing the variant to bind and spread more promptly. The BFE for the wild type NTD complex was calculated to be -65.76 kcal/mol, while the A.30 NTD complex was estimated to be -49.35 kcal/mol. This shows the impact of the reported substitutions and deletions in the NTD of A.30 variant, which consequently reduce the binding of mAb, allowing it to evade the immune response of the host. The reported results will aid the development of cross-protective drugs against SARS-CoV-2 and its variants., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Reports of new variants that potentially increase virulence and viral transmission, as well as reduce the efficacy of available vaccines, have recently emerged. In this study, we computationally analyzed the N439K, S477 N, and T478K variants for their ability to bind Angiotensin-converting enzyme 2 (ACE2). We used the protein-protein docking approach to explore whether the three variants displayed a higher binding affinity to the ACE2 receptor than the wild type. We found that these variants alter the hydrogen bonding network and the cluster of interactions. Additional salt bridges, hydrogen bonds, and a high number of non-bonded contacts (i.e., non-bonded interactions between atoms in the same molecule and those in other molecules) were observed only in the mutant complexes, allowing efficient binding to the ACE2 receptor. Furthermore, we used a 2.0-μs all-atoms simulation approach to detect differences in the structural dynamic features of the resulting protein complexes. Our findings revealed that the mutant complexes possessed stable dynamics, consistent with the global trend of mutations yielding variants with improved stability and enhanced affinity. Binding energy calculations based on molecular mechanics/generalized Born surface area (MM/GBSA) further revealed that electrostatic interactions principally increased net binding energies. The stability and binding energies of N439K, S477 N, and T478K variants were enhanced compared to the wild-type-ACE2 complex. The net binding energy of the systems was -31.86 kcal/mol for the wild-type-ACE2 complex, -67.85 kcal/mol for N439K, -69.82 kcal/mol for S477 N, and -69.64 kcal/mol for T478K. The current study provides a basis for exploring the enhanced binding abilities and structural features of SARS-CoV-2 variants to design novel therapeutics against the virus., (Copyright © 2021 Elsevier Ltd. All rights reserved.)