title: Capping amyloid β-sheets of the tau-amyloid structure VQIVYK with hexapeptides designed to arrest growth. An ONIOM and density functional theory study.
abstract: We present ONIOM calculations using density functional theory (DFT) as the high and AM1 as the medium level that explore the abilities of different hexapeptide sequences to terminate the growth of a model for the tau-amyloid implicated in Alzheimer's disease. We delineate and explore several design principles (H-bonding in the side chains, using antiparallel interactions on the growing edge of a parallel sheet, using all-d residues to form rippled interactions at the edge of the sheet, and replacing the H-bond donor N-H's that inhibit further growth) that can be used individually and in combination to design such peptides that will have a greater affinity for binding to the parallel β-sheet of acetyl-VQIVYK-NHCH3 than the natural sequence and will prevent another strand from binding to the sheet, thus providing a cap to the growing sheet that arrests further growth. We found peptides in which the Q is replaced by an acetyllysine (aK) residue to be particularly promising candidates, particularly if the reverse sequence (KYVIaKV) is used to form an antiparallel interaction with the sheet.
authors.affiliation: Department of Chemistry Hunter College and the Graduate School, City University of New York , 695 Park Avenue, New York, New York 10065, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Plumley
authors.forename: Jorge
authors.initials: J
authors.lastname: Ali-Torres
authors.forename: Gabor
authors.initials: G
authors.lastname: Pohl
authors.forename: J J
authors.initials: JJ
authors.lastname: Dannenberg
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D017433:Protein Structure, Secondary; D011789:Quantum Theory; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins