Structural Diversity and Initial Oligomerization of PrP106–126 Studied by Replica-Exchange and Conventional Molecular Dynamics Simulations

Abstract

Prion diseases are marked by cerebral accumulation of the abnormal isoform of the prion protein. A fragment of prion protein composed of residues 106–126 (PrP106–126) exhibits similar properties to full length prion and plays a key role in the conformational conversion from cellular prion to its pathogenic pattern. Soluble oligomers of PrP106–126 have been proposed to be responsible for neurotoxicity. However, the monomeric conformational space and initial oligomerization of PrP106–126 are still obscure, which are very important for understanding the conformational conversion of PrP106–126. In this study, replica exchange molecular dynamics simulations were performed to investigate monomeric and dimeric states of PrP106–126 in implicit solvent. The structural diversity of PrP106–126 was observed and this peptide did not acquire stable structure. The dimeric PrP106–126 also displayed structural diversity and hydrophobic interaction drove the dimerization. To further study initial oligomerization of PrP106–126, 1 µs conventional molecular dynamics simulations of trimer and tetramer formation were carried out in implicit solvent. We have observed the spontaneous formation of several basic oligomers and stable oligomers with high β-sheet contents were sampled in the simulations of trimer and tetramer formation. The β-hairpin formed in hydrophobic tail of PrP106–126 with residues 118–120 in turn may stabilize these oligomers and seed the formation oligomers. This study can provide insight into the detailed information about the structure of PrP106–126 and the dynamics of aggregation of monomeric PrP106–126 into oligomers in atomic level.

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

“…Prion protein : The study of PrP(106–126) by Ning et al . also describes the formation of the trimer and the tetramer.…”

“…PrP is such ap eptide and was studied in an all-atom REMD simulation. [173] The results of this study indicated that the dimerizationw as driven by hydrophobic interactions; however,t he conformational flexibility was similart ot hat of the monomer,w ith no increasei nb-sheet content observed. From ac oarse-grained simulation of the larger PrP(121-231)p rotein it was concluded that very little intermolecular b-sheet structure could be observed in the dimer intermediate.…”

“…Prion protein : As is often the case in experiments, peptide fragments of larger proteins that retain amyloidogenic properties are also used in MD simulations. PrP(106–126) is such a peptide and was studied in an all‐atom REMD simulation . The results of this study indicated that the dimerization was driven by hydrophobic interactions; however, the conformational flexibility was similar to that of the monomer, with no increase in β‐sheet content observed.…”

“…This observation lends further support to the claim that amyloid oligomerization proceeds through β‐sheet assembly rather than through a phase transition, as we have already discussed for hIAPP . However, another REMD study testing the aggregation of PrP(106–126) into dimers, trimers, and tetramers reveals that aggregation involves the formation of disordered oligomers . At the current stage it is not possible to determine which of the two aggregation pathways is the prevailing one.…”

“…In this model, Ala116 is predicted to be in the middle of the turn, and this is in agreement with the fibril model in (C). This fibril is part of the fibrillar model of PrP(90–231) and corresponds to the blue residues shown in Figure C. The hairpin model in (B) was obtained from REMD simulations of PrP(106–126) trimers and has Gly119 at the center of the turn. For larger oligomers, extended β‐strands with a ≈90° kink at His111/Met112 as shown in (D) are predicted by NMR measurements .…”