Aβ40-Lactam(D23/K28) models a conformation highly favorable for nucleation of amyloid

Recent solid-state NMR data (1) demonstrate that A beta(1-40) adopts a conformation in amyloid fibrils with two in-register, parallel P-sheets, connected by a bend structure encompassing residues D(23)VGSNKG(29), with a close contact between the side chains of Asp23 and Lys28. We hypothesized that forming this bend structure might be rate-limiting in fibril formation, as indicated by the lag period typically observed in the kinetics of A beta(1-40) fibrillogenesis. We synthesized A beta(1-40)-Lactam(D23/K28), a congener A beta(1-40) peptide that contains a lactam bridge between the side chains of Asp23 and Lys28. A beta(1-40)-Lactam(D23/K28) forms fibrils similar to those formed by A beta(1-40). The kinetics of fibrillogenesis, however, occur without the typical lag period, and at a rate; approximate to 1000-fold greater than is seen with A beta(1-40) fibrillogenesis. The strong tendency toward self-association is also shown by size exclusion chromatography in which A beta(1-40)-Lactam(D23/K28) forms oligomers even at concentrations of approximate to 1-5 mu M. Under the same conditions, A beta(1-40) shows no detectable oligomers by size exclusion chromatography. Our data suggest that A beta(1-40)-Lactam(D23/K28) could bypass an unfavorable folding step in fibrillogenesis, because the lactam linkage "preforms" a bendlike structure in the peptide. Consistent with this view A beta(1-40) growth is efficiently nucleated by A beta(1-40)-Lactam(D23/K28) fibril seeds.