A Multiscale Approach to Characterize the Early Aggregation Steps of the Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35

Abstract

The self-organization of peptides into amyloidogenic oligomers is one of the key events for a wide range of molecular and degenerative diseases. Atomic-resolution characterization of the mechanisms responsible for the aggregation process and the resulting structures is thus a necessary step to improve our understanding of the determinants of these pathologies. To address this issue, we combine the accelerated sampling properties of replica exchange molecular dynamics simulations based on the OPEP coarse-grained potential with the atomic resolution description of interactions provided by all-atom MD simulations, and investigate the oligomerization process of the GNNQQNY for three system sizes: 3-mers, 12-mers and 20-mers. Results for our integrated simulations show a rich variety of structural arrangements for aggregates of all sizes. Elongated fibril-like structures can form transiently in the 20-mer case, but they are not stable and easily interconvert in more globular and disordered forms. Our extensive characterization of the intermediate structures and their physico-chemical determinants points to a high degree of polymorphism for the GNNQQNY sequence that can be reflected at the macroscopic scale. Detailed mechanisms and structures that underlie amyloid aggregation are also provided.

Driving Forces and Structural Determinants of Steric Zipper Peptide Oligomer Formation Elucidated by Atomistic Simulations

“…51,52 The desolvation of nonpolar surface and formation of inter-peptide backbone hydrogen bonds was found concomitantly. 52,54,58,59 Dynamical reorganization via sliding, reptation or flipping of individual strands as opposed to repeated dissociation and annealing has been observed in simulations 48,50,54,60 and has found experimental validation. 61 Furthermore, the initial stages of assembly are reported to be likely under kinetic control, and a multiplicity of association and interconversion pathways gives rise to polymorphic aggregate structures.…”

“…61 Furthermore, the initial stages of assembly are reported to be likely under kinetic control, and a multiplicity of association and interconversion pathways gives rise to polymorphic aggregate structures. 50,59,62,63 In the context of the clearly very complex underlying free-energy landscape, the prominent and crucial role of water in the aggregation process has been highlighted. 42,[57][58][59]64,65 Here, we perform unbiased, atomistic simulations of steric zipper peptide oligomerization in explicit solvent as model systems for amyloidogenic aggregation.…”

“…50,59,62,63 In the context of the clearly very complex underlying free-energy landscape, the prominent and crucial role of water in the aggregation process has been highlighted. 42,[57][58][59]64,65 Here, we perform unbiased, atomistic simulations of steric zipper peptide oligomerization in explicit solvent as model systems for amyloidogenic aggregation. The studied peptides are short segments identified from the fibril-forming proteins tau ( 306 VQIVYK 311 , referred to as PHF6), 15,24 insulin ( 12 VEALYL 17 , referred to as IB12) 5,15 and α-synuclein ( 51 GVATVA 56 , referred to as AS51).…”

Exploring the role of hydration and confinement in the aggregation of amyloidogenic peptides Aβ16−22 and Sup357−13 in AOT reverse micelles

“…Electronic mail: straub@bu.edu hanced bulk protein concentration, 6 enhanced sampling methods ((Replica Exchange Molecular Dynamics, coarse-grained models), [7][8][9] and studying various lengths and segments of the amyloidogenic proteins. [10][11][12][13][14][15][16] One particularly promising approach is the confinement of aggregation-prone proteins within a reverse micelle environment. [17][18][19] Reverse micelles (RMs) provide an important environment for the study of protein folding and aggregation.…”

Practical Estimation of TCR-pMHC Binding Free-Energy Based on the Dielectric Model and the Coarse-Grained Model

“…OPEP model all the atoms of main chain and maps one bead for side chain. As can be guessed, this models is suitable for dealing with the issues where backbone structure such as -helix and -sheet play essential roles , Laghaei et al 2011, Nasica-Labouze et al 2011) (E).…”