title: Folding events in the 21-30 region of amyloid beta-protein (Abeta) studied in silico.
abstract: Oligomeric assemblies of the amyloid beta-protein (Abeta) have been implicated in the pathogenesis of Alzheimer's disease as a primary source of neurotoxicity. Recent in vitro studies have suggested that a 10-residue segment, Ala-21-Ala-30, forms a turn-like structure that nucleates the folding of the full-length Abeta. To gain a mechanistic insight, we simulated Abeta(21-30) folding by using a discrete molecular dynamics algorithm and a united-atom model incorporating implicit solvent and a variable electrostatic interaction strength (EIS). We found that Abeta(21-30) folds into a loop-like conformation driven by an effective hydrophobic attraction between Val-24 and the butyl portion of the Lys-28 side chain. At medium EIS [1.5 kcal/mol (1 cal = 4.18 J)], unfolded conformations almost disappear, in agreement with experimental observations. Under optimal conditions for folding, Glu-22 and Asp-23 form transient electrostatic interactions (EI) with Lys-28 that stabilize the loop conformations. Glu-22-Lys-28 is the most favored interaction. High EIS, as it occurs in the interior of proteins and aggregates, destabilizes the packing of Val-24 and Lys-28. Analysis of the unpacked structures reveals strong EI with predominance of the Asp-23-Lys-28 interaction, in agreement with studies of molecular modeling of full-length Abeta fibrils. The binary nature of the EI involving Lys-28 provides a mechanistic explanation for the linkage of amino acid substitutions at Glu-22 with Alzheimer's disease and cerebral amyloid angiopathy. Substitutions may alter the frequency of Glu-22 or Asp-23 involvement in contact formation and affect the stability of the folding nucleus formed in the Abeta(21-30) region.
authors.affiliation: Center for Polymer Studies and Department of Physics, Boston University, Boston, MA 02215, USA. jmborr@bu.edu
authors.forename: Jose M
authors.initials: JM
authors.lastname: Borreguero
authors.forename: Brigita
authors.initials: B
authors.lastname: Urbanc
authors.forename: Noel D
authors.initials: ND
authors.lastname: Lazo
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Buldyrev
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.forename: H Eugene
authors.initials: HE
authors.lastname: Stanley
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001665:Binding Sites; D010446:Peptide Fragments / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013499:Surface Properties
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C501831:amyloid beta-protein (21-30)