The Effect of Pro28Thr Point Mutation on the Local Structure and Stability of Human Galactokinase Enzyme – A Theoretical Study

TitleThe Effect of Pro28Thr Point Mutation on the Local Structure and Stability of Human Galactokinase Enzyme – A Theoretical Study
Publication TypeJournal Article
Year of Publication2011
AuthorsJojart B, Szori M, Izsak R, Marsi I, Laszlo A, Csizmadia IG, Viskolcz B
JournalJournal of Molecular Modeling
Volume17
Pagination2639-2649
Date PublishedJAN 25
Abstract

Galactokinase is responsible for the phosphorylation of α-D-galactose which is an important step in the metabolism of the latter. It’s malfunctioning due to a single point mutations causes cataracta, and in serious cases blindness. In this paper the Pro28Thr point mutation was studied using a variety of theories including molecular dynamics, MM-PBSA/GBSA calculations and AIM analysis. Altered H bonding networks were detected based on geometric and electron density criteria which resulted in local unfolding in the β‑sheet secondary structure. Another consequence was the decrease in stability (5-7 kcal mol-1) around this region which was confirmed by ΔGbind calculations for the extracted part of the whole system. Local unfolding was verified by several other molecular dynamics simulations performed with different duration, initial velocities and force field. Based on these results we have proposed a possible mechanism for the unfolding caused by the Pro28Thr point mutation.