Folding and membrane insertion of amyloid-beta (25-35) peptide and its mutants: Implications for aggregation and neurotoxicity

Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/50710

Title:	Folding and membrane insertion of amyloid-beta (25-35) peptide and its mutants: Implications for aggregation and neurotoxicity
Authors:	Tsai,HHG;Lee,JB;Tseng,SS;Pan,XA;Shih,YC
Contributors:	化學學系
Keywords:	MOLECULAR-DYNAMICS SIMULATIONS;SIDE-CHAIN INTERACTIONS;FREE-ENERGY LANDSCAPE;LIPID-BILAYERS;ALZHEIMERS-DISEASE;FIBRIL FORMATION;PRION PROTEIN;SECONDARY STRUCTURE;FORMING PEPTIDE;SHEET STRUCTURE
Date:	2010
Issue Date:	2012-03-27 18:08:32 (UTC+8)
Publisher:	國立中央大學
Abstract:	The mechanisms of interfacial folding and membrane insertion of the Alzheimer's amyloid-beta fragment A beta(25-35) and its less toxic mutant, N27A-A beta(25-35) and more toxic mutant, M35A-A beta(25-35), are investigated using replica-exchange molecular dynamics in an implicit water-membrane environment. This study simulates the processes of interfacial folding and membrane insertion in a spontaneous fashion to identify their general mechanisms. A beta(25-35) and N27A-A beta(25-35) peptides share similar mechanisms: the peptides are first located in the membrane hydrophilic region where their C-terminal residues form helical structures. The peptides attempt to insert themselves into the membrane hydrophobic region using the C-terminal or central hydrophobic residues. A small portion of peptides can successfully enter the membrane's hydrophobic core, led by their C-terminal residues, through the formation of continuous helical structures. No detectable amount of M35A-A beta(25-35) peptides appeared to enter the membrane's hydrophobic core. The three studied peptides share a similar helical structure for their C-terminal five residues, and these residues mainly buried within the membrane's hydrophobic region. In contrast, their N-terminal properties are markedly different. With respect to the A beta(25-35), the N27A-A beta(25-35) forms a more structured helix and is buried deeper within the membrane, which may result in a lower degree of aggregation and a lower neurotoxicity; in contrast, the less structured and more water-exposed M35A-A beta(25-35) is prone to aggregation and has a higher neurotoxicity. Understanding the mechanisms of A beta peptide interfacial folding and membrane insertion will provide new insights into the mechanisms of neurodegradation and may give structure-based clues for rational drug design preventing amyloid associated diseases.
Relation:	PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
Appears in Collections:	[Department of Chemistry] journal & Dissertation

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