ScholarWorks@숙명여자대학교

초록

Extracellular deposition of amyloid-beta (A beta) protein, a fragment of membrane glycoprotein called beta-amyloid precursor transmembrane protein (beta APP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Ab 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 (A beta 42) in explicit water to characterize most plausible aggregation-prone structure (APS) for the monomer and the very early conformational transitions for A beta 42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of A beta 42 misfolding in water, the APS for A beta 42 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 A beta 42 allow us to provide new insight into the higher aggregation propensity of A beta 42 over A beta 40, 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 A beta 42 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 A beta 42 aggregation process to cause AD. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 32: 349-355, 2011

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