Unraveling the impact of ORF3a Q57H mutation on SARS-CoV-2: insights from molecular dynamics


Chemistry and Biochemistry

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ORF3a is a conserved accessory protein of SARS-CoV-2, linked to viral infection and pathogenesis, with acquired mutations at various locations. Previous studies have shown that the occurrence of the Q57H mutation is higher in comparison to other positions in ORF3a. This mutation is known to induce conformational changes, yet the extent of structural alteration and its role in the viral adaptation process remain unknown. Here we performed molecular dynamics (MD) simulations of wt-ORF3a, Q57H, and Q57A mutants to analyze structural changes caused by mutations compared to the native protein. The MD analysis revealed that Q57H and Q57A mutants show significant structural changes in the dimer conformation than the wt-ORF3a. This dimer conformer narrows down the ion channel cavity, which reduces Na + or K + permeability leading to decrease the antigenic response that can help the virus to escape the host immune system. Non-bonding interaction analysis shows the Q57H mutant has more interacting residues, resulting in more stability within dimer conformation than the wt-ORF3a and Q57A. Moreover, both mutant dimers (Q57H and Q57A) form a novel salt-bridge interaction at the same position between A:Asp142 and B:Lys61, whereas such an interaction is absent in the wt-ORF3a dimer. We have also noticed that the TM3 domain’s flexibility in Q57H is increased because of strong inter-domain interactions of TM1 and TM2 within the dimer conformation. These unusual interactions and flexibility of Q57H mutant can have significant impacts on the SARS-CoV-2 adaptations, virulence, transmission, and immune system evasion. Our findings are consistent with the previous experimental data and provided details information on the structural perturbation in ORF3a caused by mutations, which can help better understand the structural change at the molecular level as well as the reason for the high virulence properties of this variant. Communicated by Ramaswamy H. Sarma.

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Journal of Biomolecular Structure and Dynamics

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