Capping Parallel β-Sheets of Acetyl(Ala)(6)NH(2) with an Acetyl(Ala)(5)ProNH(2) Can Arrest the Growth of the Sheet, Suggesting a Potential for Curtailing Amyloid Growth. An ONIOM and Density Functional Theory Study

[Image: see text] We present ONIOM calculations using B3LYP/d95(d,p) as the high level and AM1 as the medium level on parallel β-sheets containing four strands of Ac-AAAAAA-NH(2) capped with either Ac-AAPAAA-NH(2) or Ac-AAAPAA-NH(2). Because Pro can form H-bonds from only one side of the peptide linkage (that containing the C=O H-bond acceptor), only one of the two Pro-containing strands can favorably add to the sheet on each side. Surprisingly, when the sheet is capped with AAPAAA-NH(2) at one edge, the interaction between the cap and sheet is slightly more stabilizing than that of another all Ala strand. Breaking down the interaction enthalpies into H-bonding and distortion energies shows the favorable interaction to be due to lower distortion energies in both the strand and the four-stranded sheet. Because another strand would be inhibited for attachment to the other side of the capping (Pro-containing) strand, we suggest the possible use of Pro residues in peptides designed to arrest the growth of many amyloids.