Location and Conformation of Amyloid ß(25-35) Peptide and its Sequence-Shuffled Peptides within Membranes: Implications for Aggregation and Toxicity in PC12 Cells.

ChemMedChem

PubMedID: 24729535

Tsai HH, Lee JB, Shih YC, Wan L, Shieh FK, Chen CY. Location and Conformation of Amyloid ß(25-35) Peptide and its Sequence-Shuffled Peptides within Membranes: Implications for Aggregation and Toxicity in PC12 Cells. ChemMedChem. 2014;.
Extracellular deposits of amyloid ß (Aß) 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 Aß fragments, wild-type Aß(25-35), Aß(35-25), and a sequence-shuffled peptide [Aß(25-35)-shuffled] from Aß(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 Aß peptides.