Comparative mutational analysis of SARS-CoV-2 isolates from Pakistan and structural-functional implications using computational modelling and simulation approaches

• Published in: Computers in biology and medicine 2022-02, Vol.141, p.105170-105170, Article 105170
• Main Authors: Shah, Abdullah, Rehmat, Saira, Aslam, Iqra, Suleman, Muhmmad, Batool, Farah, Aziz, Abdul, Rashid, Farooq, Midrarullah, Nawaz, Muhmmad Asif, Ali, Syed Shujait, Junaid, Muhammad, Khan, Abbas, Wei, Dong-Qing
• Format: Article
• Language: English
• Subjects: ACE2; Amino acids; Angiotensin-converting enzyme 2; Computer applications; Coronaviruses; COVID-19; COVID-19 - virology; COVID-19 vaccines; Disease transmission; Drug development; Genome, Viral; Genomes; Humans; Infectivity; Influenza; Molecular docking; Molecular Docking Simulation; Mutation; Nucleocapsids; Pakistan; Pathogenesis; Phosphorylation serine/threonine kinases; Proteins; RNA polymerase; RNA viruses; SARS-CoV-2; SARS-CoV-2 - genetics; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Simulation; Spike Glycoprotein, Coronavirus - genetics; Spike protein; Structural proteins; Structural stability; Structure-function relationships; Vaccines; Viral diseases; Viral infections; Viruses
• ISSN: 0010-4825; 1879-0534; 1879-0534
• DOI: 10.1016/j.compbiomed.2021.105170

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 (KD), 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. •The SARS-CoV-2, being RNA virus, is prone to high mutations since its first emergence in Wuhan city of China as it spread.•The current study explored the mutation profile 250 Pakistani isolates of the SARS-CoV-2 genomes.•We found that structural proteins mainly exhibit more mutations than the others in Pakistani isolates.•We observed that these mutations decreased the structural stability altered different biological pathways.•Our analysis results also showed that coding genes can be targeted for vaccine and drug development.