Spontaneous beta-helical fold in prion protein: the case of PrP(82-146).

The presence of amyloid is a hallmark of Gerstmann-Sträussler-Scheinker (GSS) disease, which is a prion disease caused by germ line mutations in the PRNP gene. The major component of amyloid is a fragment spanning residues from 81-82 to 144-153, part of the minimal sequence thought to play a crucial role in the conversion reaction and to sustain prion replication. We present here a molecular dynamics study on the 82-146 peptide from the human prion protein. The aim is to identify its aggregation-prone folds. The 82-146 prion sequence corresponds to a naturally occurring prion peptide able to form fibrils rich in parallel beta-sheets. A spontaneous right-handed beta-helical arrangement with 13 residues per turn can be observed in the 103-135 segment of the 82-146 peptide. The observed fold is in accordance with the evidence of a parallel beta-sheet organization in amyloid and with experiments on 82-146 discussed in the literature. To elucidate the conformational properties that trigger this peptide's aggregation propensity, the conformational behavior of peptides of different length (106-126 and 113-120 prion segments) was also investigated. Simulation analysis has led to some interesting considerations on sequence specific flexibility and the effects of growth. Comparing peptides of different length allows the localization of the origin of the beta-helix conformational propensity in the 106-126 segment, though longer sequences appear necessary for a clear beta-helical arrangement. Structural features of the observed 82-146 beta-helical fold are compatible with the "dock and lock" mechanism proposed to interpret peptide aggregation kinetics.