Understanding Aβ dimer/inhibitor interactions from computer simulations

Aggregation of the Amyloid β-protein (Aβ) peptide is one key feature in Alzheimer’s disease (AD). Growing evidence supports that Aβ oligomers are the major causative agents leading to neural cell death in Alzheimer’s disease. The polyphenol (-)-epigallocatechin gallate (EGCG) and 1,4-naphthoquinon-2...

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Bibliographic Details
Main Author: Zhang, Tong
Other Authors: Mu Yuguang
Format: Theses and Dissertations
Language:English
Published: 2015
Subjects:
Online Access:http://hdl.handle.net/10356/65311
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Institution: Nanyang Technological University
Language: English
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Summary:Aggregation of the Amyloid β-protein (Aβ) peptide is one key feature in Alzheimer’s disease (AD). Growing evidence supports that Aβ oligomers are the major causative agents leading to neural cell death in Alzheimer’s disease. The polyphenol (-)-epigallocatechin gallate (EGCG) and 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp) molecules have been reported to alter Aβ self-assembly and reduce toxicity. Given the experimental challenge to characterize the structures of Aβ/inhibitor complexes, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1-42 dimer with EGCG or NQTrp in explicit solvent. Our equilibrium Aβ dimeric structures free of inhibitor are consistent with the collision cross-section from ion-mobility mass spectrometry and the secondary structure composition from circular dichroism experiment. In the presence of EGCG, the Aβ structures are characterized by increased inter center-of-mass distances, reduced inter-chain and intra-chain contacts, reduced β-sheet content and increased coil and α-helix contents. Analysis of the free energy surfaces reveals that the Aβ dimer with EGCG adopts new conformations, affecting therefore its propensity to adopt fibril-prone states. The interactions between NQTrp and Aβ1-42 dimer, which change the Aβ interface by reducing the intermolecular contacts between the residues 16-42, particularly the contacts involving central hydrophobic core regions, are found very dynamic and multiple, leading to many transient binding sites. The list of most favorable binding residues provides a completely different picture from in vitro and in silico experiments on NQTrp with shorter Aβ fragments. Importantly, the residues that bind to NQTrp, explain the beneficial effect of NQTrp to reduce both Aβ1-42 aggregation and toxicity. The study provides, for the first time, insights on the high resolution structures of Aβ1-42 dimer/EGCG and Aβ1-42 dimer/NQTrp complex in equilibrium, and the atomic pictures of the inhibitor-mediated conformational changes on Aβ1-42 dimer. Despite different chemical feature of EGCG and NQTrp, both molecules bind to similar residues of Aβ42 dimer. In addition, the residues are coherent with those identified from previous high-throughput study, implying the existence of common hot-spots for the binding of small molecules. Given their important roles involved in aggregation and toxicity, the hot-spot residues should provide atomic insights for drug discovery against AD.