Insights into structure, stability and toxicity of monomeric and aggregated polyglutamine models from molecular dynamics simulations

¹ Istituto di Biostrutture e Bioimmagini, CNR
² Istituto di Scienze Alimentari, CNR

^* To whom correspondence should be addressed. E-mail: luigi.vitagliano{at}unina.it.

Submitted on August 2, 2007
Revised on September 11, 2007
Accepted on 3 December 2007

	Abstract

Nine genetically inherited neurodegenerative diseases are linked to abnormal expansions of a polyglutamine (polyQ) encoding region. Over the years, several structural models for polyQ regions have been proposed and confuted. The cross- spine steric zipper motif, recently identified for the GNNQQNY peptide (Nelson, R., et al. 2005. Nature 435:773-778), represents an attractive model for amyloid fibers formed by polyQ fragments. Here we report a detailed molecular dynamics investigation of polyQ models assembled by cross- spine steric zipper motifs. Our simulations clearly indicate that these assemblies are very stable. Glutamine side chains strongly contribute to the overall stability of the models by perfectly fitting within the zipper. In contrast to GNNQQNY zipper motifs, hydrogen bonding interactions provide a significant contribution to the overall stability of polyQ models. Molecular dynamics simulations carried out on monomeric polyQ forms (composed by 40-60 residues) clearly show that they can also assume structures stabilized by steric zipper motifs. Based on the findings we build monomeric polyQ models that can explain recent data on the toxicity exerted by these species (Nagai, Y., et al. 2007. Nat. Struct. Mol. Biol. 14:332-340). In a more general context, our data suggests that polyQ models with interdigitated side chains can provide a structural rationale to several literature experiments on polyQ formation, stability and toxicity.

Key Words: Amyloid Structure, Computational Modeling, Conformational Diseases, Polyglutamine, Steric Zipper

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