Molecular Dynamics Simulations Studies On The Effects Of Mutations On The Binding Affinities Between SARS-CoV-2 Spike RBD And Human ACE2

The SARS-CoV-2 viruses had made a great impact on humankind and the world economy. Phylogenetic analysis revealed the newly identified B.1.617.1 and B.1.617.2 lineages possessed with few key mutations predominantly circulating. The signature mutations possessed by these lineages are situated in the RBD motif of S protein. Reports revealed variants L452R, T478K, and E484Q harbours in enhancement with hACE2 binding while P681R situated in furin cleavage site resulting in better transmissibility. To gain a deeper understanding of the impact of these variants (L452R, T478K and E484Q) binding with hACE2, structural dynamics at the interface between S-RBD protein and hACE2 were studied. We performed our dynamics studies with both single mutant complex (L452R, T478K and E484Q) and in the combination of triple mutants (L452R + T478K + E484Q) at 100ns in contrast with the wild type. Interfacial docking interactions and Molecular Mechanics approach exhibited that the spike mutants −L452R, T478K and E484Q harbour with higher binding affinity on hACE2 in contrast with its native spike protein. The presence of interfacial residue, intermolecular contacts such as hydrogen bonding, salt bridge and non-hydrogen bonded interactions might be the reason for its higher binding affinity. Hence the findings from our study unravelled plausible mechanism for the increase in affinities of mutants to hACE2 thus leading to higher transmissibility and infection of emerging variants. Further, the conformational alterations in the course of dynamics at the RBD motif led to enhancement of hACE2 binding and immune escape. These results suggest that the structural changes introduced by these variants enhance the binding affinities of the S protein with the hACE2 that could form the basis to further aid in designing therapeutics that could inhibit at the interface of S protein and hACE2 receptor.