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

Abstract

Understanding the structural and energetic requirements of non-fibrillar oligomer formation harbors the potential to decipher an important yet still elusive part of amyloidogenic peptide and protein aggregation. Low-molecular-weight oligomers are described to be transient and polymorphic intermediates in the nucleated self-assembly process to highly ordered amyloid fibers and were additionally found to exhibit a profound cytotoxicity. However, detailed structural information on the oligomeric species involved in the nucleation cannot be readily inferred from experiments. Here, we study the spontaneous assembly of steric zipper peptides from the tau protein, insulin and α-synuclein with atomistic molecular dynamics simulations on the microsecond timescale. Detailed analysis of the forces driving the oligomerization reveals a common two-step process akin to a general condensation-ordering mechanism and thus provides a rational understanding of the molecular basis of peptide self-assembly. Our results suggest that the initial formation of partially ordered peptide oligomers is governed by the solvation free energy, whereas the dynamical ordering and emergence of β-sheets are mainly driven by optimized inter-peptide interactions in the collapsed state. A novel mapping technique based on collective coordinates is employed to highlight similarities and differences in the conformational ensemble of small oligomer structures. Elucidating the dynamical and polymorphic β-sheet oligomer conformations at atomistic detail furthermore suggests complementary sheet packing characteristics similar to steric zipper structures, but with a larger heterogeneity in the strand alignment pattern and sheet-to-sheet arrangements compared to the cross-β motif found in the fibrillar or crystalline states.

Spontaneous Aggregation of the Insulin-Derived Steric Zipper Peptide VEALYL Results in Different Aggregation Forms with Common Features

“…Altogether, our results support the notion that the steric zipper is the basic motif of β-strand arrangement in various states of self-assembled VEALYL peptide aggregates with distinct morphology, thus providing a molecular picture for the generic cross-β structure of amyloids and amyloid-like assemblies [18,21,22,57].…”

In Silico Cross Seeding of Aβ and Amylin Fibril-like Oligomers

“…It has been proposed that the loop region connecting the two β-sheets of the U turn or (β arch) model of Aβ are stabilized by a salt bridge between D 23 and K 28 42,32 that prevents larger backbone motions. Hence, we also probe the effect of the salt bridge on the stability of the aggregates on the Aβ and its hetero-octamer assemblies.…”

“…Hence, we also probe the effect of the salt bridge on the stability of the aggregates on the Aβ and its hetero-octamer assemblies. The salt bridge distance is calculated as the averaged distance of the CO bonds of the carboxyl group of D 23 Figure S3, Supporting Information). Hence, the presence of these salt bridges is important for stabilizing the hydration cavity not only of the Aβ 15−40 octamers but also of the cross-seeded Aβ 15−40 |amylin 15−30 heteroassembly.…”

Computational approaches to understanding protein aggregation in neurodegeneration

“…Results of atomistic simulations (Tsigelny et al, 2008) suggest that the transient oligomers formed by a-synuclein may be the species capable of interacting with lipid membranes. A MD study of aggregation kinetics (Matthes et al, 2012) indicates a two-phase process of fibril formation, where formation of the contact interface by mostly disordered chains is followed by structural transition and accumulation of b-sheet content. It also suggests a critical role of protein-solvent interactions in a-synuclein aggregation.…”