Molecular dynamics analyses of cross-beta-spine steric zipper models: beta-sheet twisting and aggregation

Esposito  L; Pedone  C; Vitagliano  L

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Molecular dynamics analyses of cross-beta-spine steric zipper models: beta-sheet twisting and aggregation

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摘要

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 A-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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2006年第31期|11533-11538|共6页
作者
Esposito L; Pedone C; Vitagliano L;
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作者单位

CNR, Ist Biostrutt & Bioimmagini, I-80134 Naples, Italy;

Univ Naples Federico II, Dipartimento Sci Biol, Sezione Biostrutt, I-80134 Naples, Italy;

Ctr Interuniv Ric Peptidi Bioattivi, I-80134 Naples, Italy;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
amyloid fiber; prion; neurodegenerative diseases; AMYLOID-FORMING PEPTIDE; SIDE-CHAIN INTERACTIONS; YEAST PRION SUP35; RIBONUCLEASE-A; FIBRILS; PROTEIN; SIMULATIONS; ORGANIZATION; REPEATS; DISEASE;

Molecular dynamics analyses of cross-beta-spine steric zipper models: beta-sheet twisting and aggregation

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