The Spontaneous Aggregation of Steric Zipper Peptides Studied by Molecular Dynamics Simulations

Abstract

Recently obtained crystal structures of truncated fragments of proteins provide detailed structural insights into beta-sheet rich aggregates, known as amyloid fibrils [1,2]. The arrangement of these short model peptides revealed a common steric zipper motif in the crystalline state. Two sheets of peptide strands are interfaced by a dry and tight zipper structure with a high degree of sidechain complementarity. Combined experimental data suggests that steric zippers may represent a general feature of amyloid formation. However, a thorough understanding of the aggregation process and the structural characterization of its multitude of conformational states is still lacking.We employ molecular dynamics simulations in an explicit solvent environment to study biomolecular aggregation at atomistic detail with the aim to unveil the energetic and structural determinants that drive the formation of amyloidogenic peptide assemblies and also stabilize the formed aggregates.Starting from separated peptide chains with random conformations, we monitor the primary events of aggregation and find a rapid clustering of the peptides accompanied by an increased number of inter-molecular hydrogen bonds and the spontaneous formation of beta-sheet rich oligomers. Some of the peptide aggregates feature structural characteristics of the crystalline conformation (e.g. beta-sheet bilayers with dry interface), but also interconvert with conformationally distinct oligomeric states.By mapping the conformational ensembles we were able to describe the different topologies of the system, which helps to yield insight into possible common mechanistic steps found along the aggregation pathway. The goal of our work is to fully characterize the aggregation behaviour of small model peptides and test our findings with results from /in vitro/ experiments (EM, NMR) with a particular focus on aggregation-prone sequences of tau, insulin and alpha-synuclein.[1] Nelson et al., Nature, 2005[2] Sawaya et al., Nature, 2007