Folding events in the 21–30 region of amyloid -protein (A ) studied in silico

Oligomeric assemblies of the amyloid -protein (A ) 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 A . To gain a mechanistic insight, we simulated A (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 A (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 A 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 A (21–30) region.