Keywords: Amyloid Fiber, Neurodegenerative Diseases, Prion, Glycylasparaginylasparaginylglutaminylglutaminylasparaginyltyrosine, Peptide, Prion Protein, Unclassified Drug, Alzheimer Disease, Article, Beta Sheet, Crystal Structure, Crystallography, Electron Microscopy, Hydration, Molecular Dynamics, Molecular Model, Molecular Size, Priority Journal, Protein Aggregation, Protein Interaction, Protein Motif, Protein Stability, Protein Structure, Stereochemistry, Amino Acid Sequence, Computer Simulation, Molecular Sequence Data, Secondary, Genetics, Metabolism,
Affiliations: *** IBB - CNR ***
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Università degli Studi di Napoli Federico II, I-80134 Napoli, Italy
Dipartimento delle Scienze Biologiche Sezione di Biostrutture, Università degli Studi di Napoli Federico II, I-80134 Napoli, Italy
Centro Interuniversitario di Ricerca sui Peptidi Bioattivi, I-80134 Napoli, Italy
References: Not available.
Molecular dynamics analyses of cross-beta-spine steric zipper models: beta-sheet twisting and aggregation
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 beta-sheets composed of a limited number of beta-strands are stable in the 20-ns time interval considered, which suggests that steric zipper interactions at a beta-sheet-beta-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 beta-strands that compose the beta-sheets is observed. These results demonstrate that the occurrence of steric zipper interactions is compatible with flat and twisted beta-sheets. Molecular dynamics simulations carried out on two pairs of beta-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.
Molecular dynamics analyses of cross-beta-spine steric zipper models: beta-sheet twisting and aggregation
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(421 views) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 ViewExport to BibTeXExport to EndNote