Structural analysis on mutation residues and interfacial water molecules for human TIM disease understanding

BMC Bioinformatics

Research

Hung Nguyen¹  Jinyan Li¹  Qian Liu¹  Liang Zhao²  Chee Keong Kwoh²  Zhenhua Li²  Ying He²  Limsoon Wong³ 

[1] Advanced Analytics Institute and Center for Health Technologies, Faculty of Engineering and Information Technology, University of Technology Sydney, PO Box 123, 2007, NSW, Australia;School of Computer Engineering, Nanyang Technological University, 639798, Singapore;School of Computing, National University of Singapore, 117417, Singapore;

关键词: Molecular Dynamic Simulation;    Gini Coefficient;    Water Cluster;    Lorenz Curve;    Wild Type Enzyme;   

DOI  :  10.1186/1471-2105-14-S16-S11

来源: Springer

【 摘 要 】

BackgroundHuman triosephosphate isomerase (HsTIM) deficiency is a genetic disease caused often by the pathogenic mutation E104D. This mutation, located at the side of an abnormally large cluster of water in the inter-subunit interface, reduces the thermostability of the enzyme. Why and how these water molecules are directly related to the excessive thermolability of the mutant have not been investigated in structural biology.ResultsThis work compares the structure of the E104D mutant with its wild type counterparts. It is found that the water topology in the dimer interface of HsTIM is atypical, having a "wet-core-dry-rim" distribution with 16 water molecules tightly packed in a small deep region surrounded by 22 residues including GLU104. These water molecules are co-conserved with their surrounding residues in non-archaeal TIMs (dimers) but not conserved across archaeal TIMs (tetramers), indicating their importance in preserving the overall quaternary structure. As the structural permutation induced by the mutation is not significant, we hypothesize that the excessive thermolability of the E104D mutant is attributed to the easy propagation of atoms' flexibility from the surface into the core via the large cluster of water. It is indeed found that the B factor increment in the wet region is higher than other regions, and, more importantly, the B factor increment in the wet region is maintained in the deeply buried core. Molecular dynamics simulations revealed that for the mutant structure at normal temperature, a clear increase of the root-mean-square deviation is observed for the wet region contacting with the large cluster of interfacial water. Such increase is not observed for other interfacial regions or the whole protein. This clearly suggests that, in the E104D mutant, the large water cluster is responsible for the subunit interface flexibility and overall thermolability, and it ultimately leads to the deficiency of this enzyme.ConclusionsOur study reveals that a large cluster of water buried in protein interfaces is fragile and high-maintenance, closely related to the structure, function and evolution of the whole protein.

【 授权许可】

CC BY   
© Li et al.; licensee BioMed Central Ltd. 2013