10.1186/1471-2105-14-S16-S11BMC Bioinformatics14SUPPL16-BBMI

A Pekrun

A Schneider

AD MacKerell

AD Mackerell

AS Schneider

C Rodriguez-Almazan

Chee Keong Kwoh

F Orosz

FX Guix

H Ashkenazy

H Ponstingl

H Zhu

HM Berman

Hung Nguyen

IO Daar

J Mintseris

JC Phillips

Jinyan Li

Liang Zhao

Limsoon Wong

LLC Schrödinger

M Ralser

M Tajes

MO Lorenz

MT Reetz

O Carugo

PJ Keeling

Qian Liu

R Arya

R Wierenga

RE Linarello

RP Bahadur

S Fischer

S Hollan

S Jones

SC Mande

SL Hrizo

T Darden

W Humphrey

Ying He

Z Li

Zhenhua Li

BMC Bioinformatics

PubMed

Background: Human 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.Results: This 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.Conclusions: Our 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. © 2013 Li et al.; licensee BioMed Central Ltd

Li, Z

He, Y

Liu, Q

Zhao, L

Wong, L

Kwoh, CK

Nguyen, H

Li, J

OPUS - University of Technology Sydney

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

Background: Human 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. Results: This 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. Conclusions: Our 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.Published versio

Li, Zhenhua

He, Ying

Liu, Qian

Zhao, Liang

Wong, Limsoon

Kwoh, Chee Keong

Nguyen, Hung

Li, Jinyan

Digital Repository - Nanyang Technological University

Crossref

English

DR-NTU (Digital Repository of NTU)

https://opus.lib.uts.edu.au/bitstream/10453/30638/1/2013001830OK.pdf

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

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OPUS - University of Technology Sydney

Digital Repository - Nanyang Technological University

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DR-NTU (Digital Repository of NTU)