In Silico Analysis of High-Risk Missense Variants in Human ACE2 Gene and Susceptibility to SARS-CoV-2 Infection

Abstract

SARS-CoV-2 coronavirus uses for entry to human host cells a SARS-CoV receptor of the angiotensin-converting enzyme (ACE2) that catalyzes the conversion of angiotensin II into angiotensin (1-7). To understand the effect of ACE2 missense variants on protein structure, stability, and function, various bioinformatics tools were used including SIFT, PANTHER, PROVEAN, PolyPhen2.0, I. Mutant Suite, MUpro, SWISS-MODEL, Project HOPE, ModPred, QMEAN, ConSurf, and STRING. All twelve ACE2 nsSNPs were analyzed. Six ACE2 high-risk pathogenic nsSNPs (D427Y, R514G, R708W, R710C, R716C, and R768W) were found to be the most damaging by at least six software tools (cumulative score between 6 and 7) and exert deleterious effect on the ACE2 protein structure and likely function. Additionally, they revealed high conservation, less stability, and having a role in posttranslation modifications such a proteolytic cleavage or ADP-ribosylation. This in silico analysis provides information about functional nucleotide variants that have an impact on the ACE2 protein structure and function and therefore susceptibility to SARS-CoV-2.

Figure 1

ConSurf analysis of ACE2_HUMAN angiotensin-converting enzyme 2 (UniProt ID: Q9BYF1).

Figure 2

Superimposed structure of native and mutant models of the ACE2 protein. The superimposed structure of native amino acid aspartic acid (blue color) with mutant amino acid tyrosine (light blue color) at position 427. The superimposed structure of native amino acid arginine (blue color) with mutant amino acid glycine (red color) at position 514. The superimposed structure of native amino acid arginine (blue color) with mutant amino acid tryptophan (pale green color) at position 708. The superimposed structure of native amino acid arginine (blue color) with mutant amino acid cysteine (green cyan color) at position 710. The superimposed structure of native amino acid arginine (blue color) with mutant amino acid cysteine (violet color) at position 716. The superimposed structure of native amino acid arginine (blue color) with mutant amino acid tryptophan (light orange color) at position 768.

Figure 3

STRING network analysis of the ACE2 gene.