title: Location and conformation of amyloid β(25-35) peptide and its sequence-shuffled peptides within membranes: implications for aggregation and toxicity in PC12 cells.
abstract: Extracellular deposits of amyloid β (Aβ) aggregates in the brain is the hallmark of Alzheimer's disease. We present the configurations (location and conformation) and the interfacial folding and membrane insertion mechanisms of Aβ fragments, wild-type Aβ(25-35), Aβ(35-25), and a sequence-shuffled peptide [Aβ(25-35)-shuffled] from Aβ(25-35) within membranes by replica-exchange molecular dynamics simulations. Although these peptides have the same amino acid composition, simulations show they have distinct locations and conformations within membranes. Moreover, our in vitro experiments show that these peptides have distinct neurotoxicities. We rationalize the distinct neurotoxicities of these peptides in terms of their simulated locations and conformations in membranes. This work provides another view that complements the general hydrophobicity-toxicity views, to better explain the neurotoxicity of Aβ peptides.
authors.affiliation: Department of Chemistry, National Central University, No. 300, Jhongda Road, Jhong-Li City, Tao-Yuan County, 32001 Taiwan (R.O.C.). hhtsai@cc.ncu.edu.tw.
authors.forename: Hui-Hsu Gavin
authors.initials: HH
authors.lastname: Tsai
authors.forename: Jian-Bin
authors.initials: JB
authors.lastname: Lee
authors.forename: Yuan-Ci
authors.initials: YC
authors.lastname: Shih
authors.forename: Lei
authors.initials: L
authors.lastname: Wan
authors.forename: Fa-Kuen
authors.initials: FK
authors.lastname: Shieh
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D014867:Water
keywords: aggregation; amyloid β peptides; folding; molecular dynamics; neurotoxicity