Abstract
An in-depth analysis of first-wave SARS-CoV-2 genome is required to identify various mutations that significantly affect viral fitness. In the present study, we performed a comprehensive in silico mutational analysis of 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), and spike (S) proteins with the aim of gaining important insights into first-wave virus mutations and their functional and structural impact on SARS-CoV-2 proteins. Our integrated analysis gathered 6000 SARS-CoV-2 sequences and identified 92 mutations in S, 37 in RdRp, and 11 in 3CLpro regions. The impact of these mutations was also investigated using various in silico approaches. Among these, 32 mutations in S, 15 in RdRp, and 3 in 3CLpro proteins were found to be deleterious in nature and could alter the structural and functional behavior of the encoded proteins. The D614G mutation in spike and the P323Lmutation in RdRp are the globally dominant variants with a high frequency. Most of the identified mutations were also found in the binding moiety of the viral proteins which determine their critical involvement in host–pathogen interactions and may represent drug targets. Furthermore, potential CD4+ and CD8+ T cell epitopes were predicted, and their overlap with genetic variations was explored. This study also highlights several hot spots in which HLA and drug selective pressure overlap. The findings of the current study may allow a better understanding of COVID-19 diagnostics, vaccines, and therapeutics.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), one of the seven known human-infecting coronaviruses, is a highly transmissible and pathogenic virus [1]
Epitope Mapping To understand the strategies of viral immune escape, we examined the potential overlap between the reported mutations and immune-driven mutations in the S protein
Alignment of 6000 first-wave SARS-CoV-2 protein sequences with the reference sequence Wuhan-Hu-1 (Accession NC_045512) revealed 92 mutations in S, 37 in RNA-dependent RNA polymerase (RdRp), and 11 in 3C-like protease (3CLpro) regions (Table 1 and Figure 1)
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), one of the seven known human-infecting coronaviruses, is a highly transmissible and pathogenic virus [1]. It belongs to the Betacoronavirus genus and is an enveloped, positive-sense, single-stranded RNA virus [2]. Continuous changes in genetics and antigenicity of influenza viruses significantly affect vaccine efficacy. This evolving nature of viruses through gradual accumulation of mutations requires a constant updating of vaccine strains in order to make sure that the vaccines have similar or identical antigenic profiles to those of the circulating strains and are effective in controlling the disease [5,6]. Studies performed over the past few months have revealed that SARS-CoV-2 has acquired some evolving mutations in its human host [1,8]
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