Department of Computer Science
Evolution- and structure-based computational strategy reveals the impact of deleterious missense mutations on MODY 2 (maturity-onset diabetes of the young, type 2)
Heterozygous mutations in the central glycolytic enzyme glucokinase (GCK) can result in an autosomal dominant inherited disease, namely maturity-onset diabetes of the young, type 2 (MODY 2). MODY 2 is characterised by early onset: it usually appears before 25 years of age and presents as a mild form of hyperglycaemia. In recent years, the number of known GCK mutations has markedly increased. As a result, interpreting which mutations cause a disease or confer susceptibility to a disease and characterising these deleterious mutations can be a difficult task in large-scale analyses and may be impossible when using a structural perspective. The laborious and time-consuming nature of the experimental analysis led us to attempt to develop a cost-effective computational pipeline for diabetic research that isbased on the fundamentals of protein biophysics and that facilitates our understanding of the relationship between phenotypic effects and evolutionary processes. In this study, we investigate missensemutations in the GCK gene by using a wide array of evolution- and structure-based computational methods, such as SIFT, PolyPhen2, PhD-SNP, SNAP, SNPs&GO, fathmm, and Align GVGD. Based on the computational prediction scores obtained using these methods, three mutations, namely E70K,A188T, and W257R, were identified as highly deleterious on the basis of their effects on protein structure and function. Using the evolutionary conservation predictors Consurf and Scorecons, we further demonstrated that most of the predicted deleterious mutations, including E70K, A188T, and W257R, occur in highly conserved regions of GCK. The effects of the mutations on protein stability were computed using PoPMusic 2.1, I-mutant 3.0, and Dmutant. We also conducted molecular dynamics(MD) simulation analysis through in silico modelling to investigate the conformational differences between the native and the mutant proteins and found that the identified deleterious mutations alter the stability, flexibility, and solvent-accessible surface area of the protein. Furthermore, the functional role of each SNP in GCK was identified and characterised using SNPeffect 4.0, F-SNP, and FASTSNP.We hope that the observed results aid in the identification of disease-associated mutations that affect protein structure and function. Our in silico findings provide a new perspective on the role of GCK mutations in MODY2 from an evolution-based structure-centric point of view. The computational architecture described in this paper can be used to predict the most appropriate disease phenotypes for large-genome sequencing projects and to provide individualised drug therapy for complex diseases suchas diabetes. © Ivyspring International Publisher.
Diabetes, Evolutionary analysis, GCK, Missense mutations, Molecular dynamics
Source Publication Title
Ivyspring International Publisher
Link to Publisher's Edition
Priya George, D., Chakraborty, C., Syed Haneef, S., NagaSundaram, N., Chen, L., & Zhu, H. (2014). Evolution- and structure-based computational strategy reveals the impact of deleterious missense mutations on MODY 2 (maturity-onset diabetes of the young, type 2). Theranostics, 4 (4), 366-385. https://doi.org/10.7150/thno.7473