Document Detail

Characterizing amyloid-beta protein misfolding from molecular dynamics simulations with explicit water.
MedLine Citation:
PMID:  20734314     Owner:  NLM     Status:  In-Process    
Extracellular deposition of amyloid-beta (Aβ) protein, a fragment of membrane glycoprotein called β-amyloid precursor transmembrane protein (βAPP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Aβ protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all-atom molecular dynamics simulations for physiological 42-residue amyloid-beta protein (Aβ42) in explicit water to characterize most plausible aggregation-prone structure (APS) for the monomer and the very early conformational transitions for Aβ42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of Aβ42 misfolding in water, the APS for Aβ42 monomer is characterized by the observed correlation between the nonlocal backbone H-bond formation and the hydrophobic side-chain exposure. Characteristics on the nature of the APS of Aβ42 allow us to provide new insight into the higher aggregation propensity of Aβ42 over Aβ40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of Aβ42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the Aβ42 aggregation process to cause AD.
Chewook Lee; Sihyun Ham
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-23
Journal Detail:
Title:  Journal of computational chemistry     Volume:  32     ISSN:  1096-987X     ISO Abbreviation:  J Comput Chem     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-06     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9878362     Medline TA:  J Comput Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  349-55     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Wiley Periodicals, Inc.
Department of Chemistry, Sookmyung Women's University, Hyochangwon-gil 52, Yongsan-gu, Seoul 140-742, Korea.
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