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The mortality rates due to COVID-19 have been found disproportionate globally and are currently being researched. India mortality rate with a population of 1.3 billion people is relatively lowest to other countries with high infection rates. Genetic composition of circulating isolates continues to be a key determinant of virulence and pathogenesis. This study aimed to analyse the extent of divergence between genomes of Indian isolates (n=2525 as compared to reference Wuhan-1 strain and isolates from countries showing higher fatality rates including France, Italy, Belgium, and the USA. The study also analyses the impact of key mutations on interactions with angiotensin converting enzyme 2 (ACE2) and panel of neutralizing monoclonal antibodies. Using 1,44,605 spike protein sequences, global prevalence of mutations in spike protein was observed. The study suggests that SARS-CoV-2 genomes from India share consensus with global trends with respect to D614G as most prevalent mutational event (81.66% among 2525 Indian isolates). Indian isolates did not reported prevalence of N439K mutation in receptor binding motif (RBM) as compared to global isolates (0.54%). Computational docking and molecular dynamics simulation analysis of N439K mutation with respect to ACE 2 binding and reactivity with RBM targeted antibodies viz., B38, BD23, CB6, P2B-F26 and EY6A suggests that variant have relatively higher affinity with ACE 2 receptor which may support higher infectivity. The study warrants large scale monitoring of Indian isolates as SARS-CoV-2 virus is expected to evolve and mutations may appear in unpredictable way.

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