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Molecular dynamics analyses of cross-β-spine steric zipper models: β-Sheet twisting and aggregation

By Luciana Esposito, Carlo Pedone and Luigi Vitagliano

Abstract

The structural characterization of amyloid fibers is one of the most investigated areas in structural biology. The structural motif, denoted as steric zipper, recently discovered for the peptide GNNQQNY [Nelson, R., Sawaya, M. R., Balbirnie, M., Madsen, A. O., Riekel, C., Grothe, R. & Eisenberg, D. (2005) Nature 435, 773–778], is expected to exert strong influence in this field. To obtain further insights into the features of this unique structural motif, we report several molecular dynamics simulations of various GNNQQNY aggregates. Our analyses show that even pairs of β-sheets composed of a limited number of β-strands are stable in the 20-ns time interval considered, which suggests that steric zipper interactions at a β-sheet–β-sheet interface strongly contribute to the stability of these aggregates. Moreover, although the basic features of side chain–side chain interactions are preserved in the simulation, the backbone structure undergoes significant variations. Upon equilibration, a significant twist of the β-strands that compose the β-sheets is observed. These results demonstrate that the occurrence of steric zipper interactions is compatible with flat and twisted β-sheets. Molecular dynamics simulations carried out on two pairs of β-sheets, separated in the crystal state by a hydrated interface, lead to interesting results. The two pairs of sheets, while twisting, associate through stable peptide–peptide interactions. These findings provide insight into the mechanism that leads to the formation of higher aggregates. On these bases, it is possible to reconcile the crystallographic and the EM data on the size of the basic GNNQQNY fiber unit

Topics: Biological Sciences
Publisher: National Academy of Sciences
OAI identifier: oai:pubmedcentral.nih.gov:1544204
Provided by: PubMed Central
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