Molecular Insight into Conformational Transition of Amyloid beta-Peptide 42 Inhibited by (-)-Epigallocatechin-3-gallate Probed by Molecular Simulations

Liu, Fu-Feng, Dong, Xiao-Yan, He, Lizhong, Middelberg, Anton P. J. and Sun, Yan (2011) Molecular Insight into Conformational Transition of Amyloid beta-Peptide 42 Inhibited by (-)-Epigallocatechin-3-gallate Probed by Molecular Simulations. Journal of Physical Chemistry B, 115 41: 11879-11887. doi:10.1021/jp202640b


Author Liu, Fu-Feng
Dong, Xiao-Yan
He, Lizhong
Middelberg, Anton P. J.
Sun, Yan
Title Molecular Insight into Conformational Transition of Amyloid beta-Peptide 42 Inhibited by (-)-Epigallocatechin-3-gallate Probed by Molecular Simulations
Journal name Journal of Physical Chemistry B   Check publisher's open access policy
ISSN 1520-6106
Publication date 2011-10
Sub-type Article (original research)
DOI 10.1021/jp202640b
Volume 115
Issue 41
Start page 11879
End page 11887
Total pages 9
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2012
Language eng
Formatted abstract
Considerable experimental evidence indicates that (-)-epigallocatechin-3- gallate (EGCG) inhibits the fibrillogenesis of Aβ42 and alleviates its associated cytotoxicity. However, the molecular mechanism of the inhibition effect of EGCG on the conformational transition of Aβ42 remains unclear due to the limitations of current experimental techniques. In this work, molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) analysis were coupled to better understand the issue. It was found that the direct interactions between EGCG and the peptide are the origin of its inhibition effects. Specifically, EGCG molecules expel water from the surface of the Aβ42, cluster with each other, and interact directly with the peptide. The results of free energy decomposition calculated by MM-PBSA indicate that the nonpolar term contributes more than 71% to the binding free energy of the EGCG-Aβ42 complex, while polar interactions (i.e., hydrogen bonding) play a minor role. It was identified that there are 12 important residues of Aβ42 that strongly interact with EGCG (Phe4, Arg5, Phe19, Phe20, Glu22, Lys28, Gly29, Leu34-Gly37, and Ile41), while nonpolar interactions are mainly provided by the side chains of some hydrophobic residues (Phe, Met and Ile) and the main chains of some nonhydrophobic residues (Lys28 and Gly29). On the contrary, polar interactions are mainly formed by the main chain of Aβ42, of which the main chains of Gly29 and Gly37 contribute greatly. The work has thus elucidated the molecular mechanism of the inhibition effect of EGCG on the conformational transition of Aβ42, and the findings are considered critical for exploring more effective agents for the inhibition of Aβ42 fibrillogenesis. © 2011 American Chemical Society.
Keyword Free-Energy Decomposition
Linear Constraint Solver
Green Tea Polyphenol
Particle Mesh Ewald
Dynamics Simulations
Force-Field
Alzheimers-Disease
Induced Neurotoxicity
Secondary Structure
In-Silico
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
ERA 2012 Admin Only
Australian Institute for Bioengineering and Nanotechnology Publications
 
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