Journal of Molecular Modeling

, Volume 17, Issue 10, pp 2639–2649 | Cite as

The effect of a Pro28Thr point mutation on the local structure and stability of human galactokinase enzyme—a theoretical study

  • Balázs Jójárt
  • Milán Szőri
  • Róbert Izsák
  • István Marsi
  • Aranka László
  • Imre G. Csizmadia
  • Béla Viskolcz
Original Paper
First Online:
Received:
Accepted:

Abstract

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

Figure

The role of Thr28 and a water molecule in the local unfolding process around the point mutation of human galactokinase

Keywords

Human galactokinase Molecular dynamics AIM MMPBSA/GBSA Local unfolding β-sheet stability 

Abbreviations

MD

Molecular dynamics

WT

Wild-type form of galactokinase

MT

Point-mutated form of galactokinase

GALK

Galactokinase

WTA

Chain A of wild-type galactokinase

WTB

Chain B of wild-type galactokinase

MTA

Chain A of point-mutated galactokinase

MTB

Chain B of point-mutated galactokinase

AIM

Atoms in molecules theory

a.u.

Atomic unit

bcp

Bond critical points

PM

Point mutation

ΔGbind

Binding free energy

MTA2, MTA3, MTA4, MTA5

Shorter (6 ns long) MD simulation of the MTA using different initial velocities

n.p.

Not possible

ΔΔGbind

Relative binding free energy

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Notes

Acknowledgments

This work was supported by “Társadalmi Megújulás Operatív Program” (TÁMOP-4.2.1/B-09/1/KONV-2010-0005). The authors thank M. Labádi for technical support at the High Performance Computing Centre of the University of Szeged. The help of Methos L. Müller in the preparation of the graphics is acknowledged.

Supplementary material

894_2011_958_MOESM1_ESM.doc (2 mb)
ESM1 (DOC 2088 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Balázs Jójárt
    • 1
  • Milán Szőri
    • 1
  • Róbert Izsák
    • 1
  • István Marsi
    • 1
  • Aranka László
    • 2
  • Imre G. Csizmadia
    • 1
    • 3
  • Béla Viskolcz
    • 1
  1. 1.Department of Chemical InformaticsUniversity of SzegedSzegedHungary
  2. 2.Department of Pediatrics, Albert Szent-Györgyi Medical CenterUniversity of SzegedSzegedHungary
  3. 3.Department of ChemistryUniversity of TorontoTorontoCanada

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