D155Y Substitution of SARS-CoV-2 ORF3a Weakens Binding with Caveolin-1: An in silico Study

Abstract

The clinical manifestation of the recent pandemic COVID-19, caused by novel SARS-CoV-2, varies from mild to severe respiratory illness. Although environmental, demographicand co-morbidity factors have an impact on the severity of the disease, the contribution of mutations in each of the viral genes towards the degree of severity needs to be elucidated for designing better therapeutic approach against COVID-19. Here, we studied the effect of two substitutions D155Y and S171L, of ORF3a protein, found in COVID-19 patients. Using computational simulations we discovered that the substitutions at 155th and 171st positions changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein. Protein-protein docking using HADDOCK analysis revealed that out of the two observed substitutions, only the substitution of D155Y, weakened the binding affinity of ORF3a with caveolin-1. The increased fluctuation in the simulated ORF3a-caveolin-1 complex suggested a change in the virulence property of SARS-CoV-2. Importance The binding interaction of viral ORF3a protein to host caveolin-1 is essential for entry and endomembrane trafficking of SARS-CoV-2. The D155Y substitution in SARS-CoV-2 ORF3a is located near its caveolin-binding Domain IV and thus the substitution can interfere with the binding affinity of ORF3a to host caveolin-1. Our in silico study report decreased molecular stability of D155Y mutant of ORF3a and increased fluctuation of the simulated D155Y ORF3a-caveolin-1 complex. Thus, we hypothesize that the D155Y substitution could change the virulence property of SARS-CoV-2.