Effects of terminal capping on the fibrillation of short (L-Glu)n peptides.

ABSTRACT

Several homopolypeptides including poly-l-glutamic acid (PLGA) form amyloid-like fibrils under favorable physicochemical conditions. We have shown recently that even short uncapped (Glu)n peptides (for n>3) form fibrillar ß-aggregates which cross-seed with amyloid fibrils obtained from high molecular weight fractions of PLGA. Here we investigate effects of N-terminal acetylation and C-terminal amidation on the amyloidogenic tendencies of (Glu)n peptides containing 3, 4, and 5 residues. Our results based primarily on time-lapse FT-IR spectroscopy and AFM microscopy indicate that selective modifications of C-termini (and, to a lesser degree, of N-termini) decrease capacity of tetra- and pentapeptides to form fibrils. On the other hand, peptides modified at both ends appear to form fibrils as fast as unmodified analogues. In fact, the double terminal modification enables fibrillation of (Glu)3 which is not fibrillogenic in the unmodified state. The AFM data suggests that the double capping results in the aggregates becoming more tape-like or acquiring noticeable tendencies to bend. According to seeding and cross-seeding experiments, there is a high degree of promiscuity between modified and unmodified peptides. Possible mechanisms explaining how amyloidogenic propensities of (Glu)n peptides are affected by terminal modifications have been discussed.