Computational study of the potential impact of WHRN protein missense SNPs on WHRN-MYO15A protein complex interaction and their association with Usher syndrome.

Abstract

Usher syndrome is a rare genetic condition characterized by both hearing and vision impairment that occurs through mutations of multiple genes, including WHRN and MYO15A. In this computational work, we intend to explore how missense SNPs within the WHRN protein affect its interaction with the MYO15A protein, a crucial component of the Usher interactome. Therefore, the identification of missense SNPs that has a potential effect on the function of the WHRN protein was realized using various computational prediction tools, including VEP, SIFT, PolyPhen-2, CADD, REVEL, and Mutation Assessor. Further evaluation of the stability of mutated proteins was conducted through SDM2, MCSM, DeepDDG and CUP-SAT. We used ConSurf web server to identify conserved regions in the WHRN protein. Yasara and Haddock analysis tools were used to minimize the energy of protein 3D structures and to dock protein-protein complexes, respectively. and then the binding energy of the complexes was calculated through PRODIGY. Mutation pathogenicity prediction tools showed that in total, 18 missense SNPs, predicted as deleterious. However, a comprehensive analysis revealed that only SIX single nucleotide polymorphisms were predicted to be the most deleterious with high conservation and less stability. Furthermore, we conducted molecular dynamics analysis to fully comprehend the impact of these variations on the dynamic behavior of the WHRN-MYO15A protein complex, which revealed significant insights into the destabilizing effects of the deleterious SNPs impacting the protein's binding affinity and stability that occurs during the binding process of the WHRN-MYO15A protein complex.