Reference : Molecular dynamics simulation of the unfolding of the human prion protein domain unde...
Scientific journals : Other
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/3776
Molecular dynamics simulation of the unfolding of the human prion protein domain under low pH and high temperature conditions
English
Gu, Wei mailto []
Wang, T. T. []
Zhu, J. []
Shi, Y. Y. []
Liu, H. Y. []
2003
Biophysical Chemistry
Elsevier Science
104
1
79-94
Yes (verified by ORBilu)
International
0301-4622
Amsterdam
The Netherlands
[en] Four 10-ns molecular dynamics (MD) simulations of the human prion protein domain (HuPrP 125-228) in explicit water solution have been performed. Each of the simulations mimicked a different environment of the protein: the neutral pH environment was simulated with all histidine residues neutral and bearing a ND proton and with other titratable side chains charged, the weakly acidic environment was simulated with all titratable side chains charged, he strongly acidic environment was simulated with all titratable side chains protonated. The protein in neutral pH environment was simulated at both ambient (298 K) and higher (350 K) temperatures. The native fold is stable in he neutral pH/ambient temperature simulation. Through out all other simulations, a quite stable core consisted of 0-20 residues around the disulfide bond retain their initial conformations. However, the secondary structures of the Protein show changes of various degrees compared to the native fold, parts of the helices unfolded and the beta-sheets extended. Our simulations indicated that the heat-induced unfolding and acid-induced unfolding of HuPrP might follow different pathways: the initial stage of the acid-induced unfolding may include not only changes in secondary structures, but also changes in the tertiary structures. Under the strongly acidic condition, obvious tertiary structure changes take place after 10-ns simulation, the secondary structure elements and the loops becoming more parallel to each other, resulting in a compact state, which was stabilized by a large number of new, non-native side chain-side chain contacts. Such tertiary structure changes were not observed in the higher temperature simulation, and intuitively, they may favor the further extension of the beta-sheets and eventually the agglomeration of multiple protein molecules. The driving forces for this tertiary structure changes are discussed. Two additional 10-ns MD simulations, one with Asp202 protonated and the other with Glu196 protonated compared to the neutral pH simulation, were carried out. The results showed that the stability of the native fold is very subtle and can be strongly disturbed by eliminating a single negative charge at one of such key sites. Correlations of our results with previous experimental and theoretical studies are discussed. (C) 2003 Elsevier Science B.V. All rights reserved.
http://hdl.handle.net/10993/3776
10.1016/S0301-4622(02)00340-X

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