Investigation of nonsynonymous mutations in the spike protein of SARS-CoV-2 and its interaction with the ACE2 receptor by molecular docking and MM/GBSA approach

• Published in: Computers in biology and medicine 2021-08, Vol.135, p.104654-104654, Article 104654
• Main Authors: Aljindan, Reem Y., Al-Subaie, Abeer M., Al-Ohali, Ahoud I., Kumar D, Thirumal, Doss C, George Priya, Kamaraj, Balu
• Format: Article
• Language: English
• Subjects: ACE2; ACE2 receptor; Amino acids; Angiotensin; Angiotensin-Converting Enzyme 2; Binding; Binding affinity; Bioinformatics; Coagulation; Coronaviruses; COVID-19; Free energy; Genomes; Humans; Infections; Medical research; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Mutation; Nonsynonymous mutations; Pandemics; Peptides; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - genetics; Protein Binding; Proteins; Receptors; Respiratory distress syndrome; SARS-CoV-2; Septic shock; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike protein; Stability; Viral diseases; Viral infections
• ISSN: 0010-4825; 1879-0534
• DOI: 10.1016/j.compbiomed.2021.104654

COVID-19 is an infectious and pathogenic viral disease caused by SARS-CoV-2 that leads to septic shock, coagulation dysfunction, and acute respiratory distress syndrome. The spreading rate of SARS-CoV-2 is higher than MERS-CoV and SARS-CoV. The receptor-binding domain (RBD) of the Spike-protein (S-protein) interacts with the human cells through the host angiotensin-converting enzyme 2 (ACE2) receptor. However, the molecular mechanism of pathological mutations of S-protein is still unclear. In this perspective, we investigated the impact of mutations in the S-protein and their interaction with the ACE2 receptor for SAR-CoV-2 viral infection. We examined the stability of pathological nonsynonymous mutations in the S-protein, and the binding behavior of the ACE2 receptor with the S-protein upon nonsynonymous mutations using the molecular docking and MM_GBSA approaches. Using the extensive bioinformatics pipeline, we screened the destabilizing (L8V, L8W, L18F, Y145H, M153T, F157S, G476S, L611F, A879S, C1247F, and C1254F) and stabilizing (H49Y, S50L, N501Y, D614G, A845V, and P1143L) nonsynonymous mutations in the S-protein. The docking and binding free energy (ddG) scores revealed that the stabilizing nonsynonymous mutations show increased interaction between the S-protein and the ACE2 receptor compared to native and destabilizing S-proteins and that they may have been responsible for the virulent high level. Further, the molecular dynamics simulation (MDS) approach reveals the structural transition of mutants (N501Y and D614G) S-protein. These insights might help researchers to understand the pathological mechanisms of the S-protein and provide clues regarding mutations in viral infection and disease propagation. Further, it helps researchers to develop an efficient treatment approach against this SARS-CoV-2 pandemic. •Identified the most significant nonsynonymous mutations in the spike protein based on the stability.•Investigated the impact of nonsynonymous mutations in the spike protein using molecular dynamics.•Calculated the binding behavior of the spike protein upon nonsynonymous mutations with the ACE2 receptor for SAR-CoV-2 viral infection.