Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches

Abstract

Polio viral proteinase 2A performs several essential functions in genome replication. Its inhibition prevents viral replication, thus making it an excellent substrate for drug development. In this study, the three-dimensional structure of 2A protease was determined and optimized by homology modelling. To predict the molecular basis of the interaction of small molecular agonists, docking simulations were performed on a structurally diverse dataset of poliovirus 2A protease (PV2Apr°) inhibitors. Docking results were employed to identify high risk missense mutations that are highly damaging to the structure, as well as the function, of the protease. Intrinsic disorder regions (IDRs), drug binding sites (DBS), and protein stability changes upon mutations were also identified among them. Our results demonstrated dominant roles for Lys 15, His 20, Cys 55, Cys 57, Cys 64, Asp 108, Cys 109 and Gly 110, indicating the presence of various important drug binding sites of the protein. Upon subjecting these sites to single-nucleotide polymorphism (SNP) analysis, we observed that out of 155 high risk SNPs, 139 residues decrease the protein stability. We conclude that these missense mutations can affect the functionality of the 2A protease, and that identified protein binding sites can be directed for the attachment and inhibition of the target proteins.

In Silico Analysis of Effect of Non-synonymous SNPs associated with Permanent Neonatal Diabetes Mellitus on Stability and Structure of Human Insulin

“…Instead of testing thousands of SNPs, isolating deleterious ones using these tools would allow a more directed approach to epidemiological studies. Residues with highly deleterious variants could be possible candidates as drug targets (Younus et al, 2018). This analysis could be extended further to determine changes in the ligand-binding capability of the protein to definitively determine how changes in the structure affects functional characteristics.…”

“…Consequently, it is reasonable to assume that non-synonymous SNPs are likely to alter the structure of the native protein. Several studies have focused on determining the impact of deleterious SNPs on the structure of native proteins (Elkhattabi et al, 2019, Younus et al, 2018. Usually SNPs that arise in highly conserved positions can significantly affect the functional and structural characteristics of a protein, which makes these SNPs strong candidates for being associated with diseases (Younus et al, 2018).…”

“…Several studies have focused on determining the impact of deleterious SNPs on the structure of native proteins (Elkhattabi et al, 2019, Younus et al, 2018. Usually SNPs that arise in highly conserved positions can significantly affect the functional and structural characteristics of a protein, which makes these SNPs strong candidates for being associated with diseases (Younus et al, 2018). Elkhattabi et al (2019) studied the effect of SNPs on the structure of human resistin; out of 78 SNPs studied, 15 were predicted to be deleterious.…”