Predicting the impact of missense mutations on the protein structure networks: a case study on human phenylalanine hydroxylase and α-galactosidase

Missense mutations can affect protein structure and function, and contribute to variousdiseases. However, predicting the impact of a missense mutation on a specific disease may bechallenging [۱]. Computational methods that use both sequence and structure information can help toinvestigate and analyze the relationship between protein genotype and phenotype. In this study, we usedan approach based on protein structure networks [۲] to examine the correlation between the severity ofpathogenicity of missense mutations and the average changes in the vertex degree of mutated aminoacids and their neighbors. We collected data from multiple databases on the mutations, disease severity,protein stability changes, protein-protein binding affinity changes, conserved sequences, functionaldomains, and physicochemical properties of two proteins, namely, phenylalanine hydroxylase andalpha-galactosidase. We performed statistical analysis on the data and found that there was a significantrelationship between the average changes in the vertex degrees and the pathogenicity intensity of themutations (p-value ≤ ۰.۰۰۱). We also found that as the vertex degree increases, the proportion ofpathogenic mutations in high-degree vertices in the protein structure network increases, indicating thatpathogenic mutations were more likely to occur in residues with higher vertex degrees. Moreover, wefound a significant relationship between the severity of pathogenicity and various factors, includingchanges in stability, changes in protein-protein binding affinity, removal of salt bridges, removal ofcharged amino acids, replacement of an inflexible proline in an alpha-helix, and replacement of smallamino acids in buried positions. Our results suggest that network features and other factors can be usefulin predicting the pathogenicity severity of missense mutations.

کلیدواژه ها:

Missense mutation ، Protein structure network (PSN) ، Degree centrality ، Alpha galactosidase ، Phenylalanine hydroxylase ، Severety of pathogenicity