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SARS-CoV-2, an RNA virus, has been prone to high mutations since its first emergence in Wuhan, China, and throughout its spread. Its genome has been sequenced continuously by many countries, including Pakistan, but the results vary. Understanding its genomic patterns and connecting them with phenotypic features will help in devising therapeutic strategies. Thus, in this study, we explored the mutation landscape of 250 Pakistani isolates of SARS-CoV-2 genomes to check the genome diversity and examine the impact of these mutations on protein stability and viral pathogenesis in comparison with a reference sequence (Wuhan NC 045512.2). Our results revealed that structural proteins mainly exhibit more mutations than others in the Pakistani isolates; in particular, the nucleocapsid protein is highly mutated. In comparison, the spike protein is the most mutated protein globally. Furthermore, nsp12 was found to be the most mutated NSP in the Pakistani isolates and worldwide. Regarding accessory proteins, ORF3A is the most mutated in the Pakistani isolates, whereas ORF8 is highly mutated in world isolates. These mutations decrease the structural stability of their proteins and alter different biological pathways. Molecular docking, the dissociation constant (K D ), and MM/GBSA analysis showed that mutations in the S protein alter its binding with ACE2. The spike protein mutations D614G-S943T-V622F (-75.17 kcal/mol), D614G-Q677H (-75.78 kcal/mol), and N74K-D614G (-73.84 kcal/mol) exhibit stronger binding energy than the wild type (-66.34 kcal/mol), thus increasing infectivity. Furthermore, the simulation results strongly corroborated the predicted protein servers. Our analysis findings also showed that E, M, ORF6, ORF7A, ORF7B, and ORF10 are the most stable coding genes; they may be suitable targets for vaccine and drug development., (Copyright © 2021. Published by Elsevier Ltd.)

Severe Acute Respiratory Syndrome Corovirus2 (SARS-CoV-2) has been determined to be the cause of the current pandemic. Typical symptoms of patient having COVID-19 are fever, runny nose, cough (dry or not) and dyspnea. Several vaccines are available in markets that are tackling current pandemic. Many different strains of SAR-CoV-2 have been evolved with the passage of time. The emergence of VOCs particularly the B.1.351 ("South African") variant of SARS-CoV-2 has been reported to be more resistant than other SARS-CoV-2 strains to the current vaccines. Thus, the current research is focused to design multi-epitope subunit Vaccine (MEV) using structural vaccinology techniques. As a result, the designed MEV exhibit antigenic properties and possess therapeutic features that can trigger an immunological response against COVID-19. Furthermore, validation of the MEV using immune simulation and in silico cloning revealed that the proposed vaccine candidate effectively triggered the immune response. Conclusively, the developed MEV needs further wet lab exploration and could be a viable vaccine to manage and prevent COVID-19., (Copyright © 2021 Elsevier Ltd. All rights reserved.)