key: cord-0723107-e6corl7c authors: Chaudhari, Armi M; Kumar, Dinesh; Joshi, Madhvi; Patel, Amrutlal; Joshi, Chaitanya title: E156G and Arg158, Phe-157/del mutation in NTD of spike protein in B.1.617.2 lineage of SARS-CoV-2 leads to immune evasion through antibody escape date: 2021-06-21 journal: bioRxiv DOI: 10.1101/2021.06.07.447321 sha: 788b0fdc0d5319c0a707def595eb7be8369e89eb doc_id: 723107 cord_uid: e6corl7c Emerging variants of SARS-CoV-2 with better immune escape mechanisms and higher transmissibility remains a persistent threat across the globe. B.1.617.2 (Delta) variant was first emerged from Maharashtra, India in December, 2020. This variant is classified to be a major cause and concern of the second wave of COVID-19 in India. In the present study, we explored the genomic and structural basis of this variant through computational analysis, protein modelling and molecular dynamics (MD) simulations approach. B.1.617.2 variant carried E156G and Arg158, Phe-157/del mutations in NTD of spike protein. These mutations in N-terminal domain (NTD) of spike protein of B.1.617.2 variant revealed more rigidity and reduced flexibility compared to spike protein of Wuhan isolate. Further, docking and MD simulation study with 4A8 monoclonal antibody which was reported to bind NTD of spike protein suggested reduced binding of B.1.617.2 spike protein compared to that of spike protein of Wuhan isolate. The results of the present study demonstrate the possible case of immune escape and thereby fitness advantage of the new variant and further warrants demonstration through experimental evidence. Our study identified the probable mechanism through which B.1.617.2 variant is more pathogenically evolved with higher transmissibility as compared to the wild-type. India is witnessing the peak of another COVID-19 wave with over 0.32 million causalities 31 since 2020, and more than 27.4 million confirmed positive cases as per WHO reports 32 accessed on 27 th May, 2021. Genome surveillance is a powerful tool to study the viral 33 genomic profile, variants of concern and their epidemiological significance in disease at the S1/S2 boundary, furin-type cleavage site in its spike protein, which when cleaved can 53 bind and activate neuropilin receptors. Further, research studies indicate that NRP1 enhances 54 SARS-CoV-2 infectivity and is highly expressed in respiratory and olfactory epithelium [5] . suggests that they were evolved to escape the immune system of the host thereby giving them 80 the fitness advantage and thus increased spread among the population. Further, research is 81 needed to establish the mechanism of escape and potential host genetic factor that might help 82 in these evolved pathogenic viral strains of SARS-CoV-2. Furthermore, understanding of the role of virus-host interactions and immune response during 84 these SARS-CoV-2 infections will be pivotal to ultimately meet these evolving challenges. 85 Eventually, efficacy of the combined innate and adaptive responses is on the host's side, 86 while the virulence and its capacity to evade the host's immune responses is on the virus' side, 87 together, the balance between them dictate the disease outcome in the context of the host- Variants of Spike protein from SARS-CoV-2 were taken into study. Mutated spike from 97 SARS-CoV-2 used in this study were derived from amino acid sequence submitted in 98 GAISAD with accession number EPI_ISL_2001211. Reference protein with PDB id 7KRQ 99 was used for homology modelling. Missing side chains were added through PRIME and pKa refinement was done with epik [18]. Protein structures were refined using OPLS4 force field and altered hydrogen bonds 109 were refilled using structure refinement panel implemented in Schrodinger [19] [20]. Particle 110 mesh Ewald method is applied to calculate long rage electrostatic interactions. [21] . The Protein-protein complex system seems to have stable RMSD pattern after 60ns. These frames Mutations in NTD were covering the binding domain for monoclonal antibodies (Figure 2A ). PDB id 7CL2 was chosen as a wild-type complex of spike with 4A8 monoclonal antibody. The authors declare that they have no known competing financial interests or personal 326 relationships that could have appeared to influence the work reported in this paper. 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