Abstract
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.
Keywords: ACE2 receptor; Binding affinity; Nonsynonymous mutations; SARS-CoV-2; Spike protein; Stability.
【저자키워드】 SARS-CoV-2, ACE2 receptor, binding affinity, Spike protein, stability, Nonsynonymous mutations, 【초록키워드】 COVID-19, Treatment, viral infection, ACE2, Mutation, SAR-CoV-2, acute respiratory distress syndrome, spike, SARS-CoV, SARS-CoV-2 pandemic, bioinformatics, Infection, molecular docking, ACE2 receptor, docking, molecular dynamics, molecular mechanism, binding free energy, MERS-CoV, angiotensin-converting enzyme 2, binding affinity, Spike protein, Molecular dynamics simulation, free energy, stability, Receptor-binding domain, RBD, N501Y, Septic shock, spike-protein, D614G, mutants, viral disease, mutant, receptor, infectious, disease, binding, acute respiratory distress, Interaction, S-protein, angiotensin, Nonsynonymous mutations, respiratory distress, coagulation dysfunction, approaches, Perspective, domain, human cells, syndrome, help, pathogenic, virulent, human cell, L18F, researcher, Host, approach, MDs, pathological mechanism, G476S, nonsynonymous mutation, responsible, develop, examined, caused, investigated, screened, in viral, interact, reveal, 【제목키워드】 Spike protein, investigation, Interaction, approach, nonsynonymous mutation, the spike protein,