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

Abstract

, 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 ␤-sheets composed of a limited number of ␤-strands are stable in the 20-ns time interval considered, which suggests that steric zipper interactions at a ␤-sheet-␤-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 ␤-strands that compose the ␤-sheets is observed. These results demonstrate that the occurrence of steric zipper interactions is compatible with flat and twisted ␤-sheets. Molecular dynamics simulations carried out on two pairs of ␤-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.amyloid fiber ͉ prion ͉ neurodegenerative diseases T he insurgence of severe neurodegenerative diseases, which include Alzheimer's disease, type-II diabetes, systemic amyloidosis, and transmissible spongiform encephalopathies, is commonly associated with the presence of amyloid fibers (1-4). Intriguingly, the soluble, often globular, precursors of these ordered deposits do not share any sequence͞structure similarity. Extensive structural investigations carried out on the soluble forms of proteins involved in neurodegenerative diseases have provided a large amount of information on these forms (5-7). In contrast, limited information has been collected for the insoluble aggregates (8-10). Indeed, the intimate nature of these aggregates prevents their detailed characterization.The presence in the fiber diffraction pattern of these aggregates of strong reflections at 4.8-Å and at 10-to 11-Å resolution has led to the commonly accepted notion that a cross-␤-spine represents the basic structural motif of amyloid fibers (10, 11). Nevertheless, the complete structural definition of these aggregates is still highly debated. Over the years, several models, essentially variations on a common theme (cross-␤-spine), have been proposed (12).The use of model peptides whose solid aggregates display most of the features associated with the amyloid fibers has proved to be an important strategy used to overcome these difficulties (7, 13). Particularly impressive are the results achieved in the structural characterization of the peptide GNNQQNY derived from the prion-determining domain of the yeast protein Sup35 (14). The solid aggregates of this peptide show all of the properties associated with amyloid fibrils:...

Relationship between structural composition and material properties of polymorphic hIAPP fibrils

“…During the stacking process of the hIAPP structure, we stacked the polymorphic structures sustained with steric zipper interaction to avoid penetration of water molecules between facing two cross β strands. In this process, the intersheet interaction was sustained as dry interfaces and no water molecules between facing β strands were found, also shown in Esposito et al [10].…”

“…Furthermore, the thickness variation of amyloid fibrils as well as the number of protofibril structure were observed [9]. These amyloid proteins share cross β structures sustained with steric zipper interaction that renders them difficult to degrade in physiological environments [10][11][12][13]. Thus, understanding the stability of amyloid proteins has been recognized as a crucial step in elucidating the mechanisms of degenerative and neuro-degenerative diseases and providing treatment for these diseases.…”

Computational Simulations of the Early Steps of Protein Aggregation

“…Because of the integration 2 fs timestep, all-atom MD in explicit solvent is limited to trajectories of 1 ms-typically about 100 ns. Such a time scale might be sufficient to study the stability of preformed structures [28][29][30][31][32][33][34] such as the cross-beta-spine steric zipper of the Sup-35 prion fragment, 7,35 the very early events in the dynamics of Ab [36][37][38][39][40] or the docking of unstructured monomer on preformed structured oligomers, 41 but other methods of various degrees of efficiency and accuracy are needed to span the aggregation regime from monomers to fibrils, which requires several days in vitro.…”

Atomic structures of peptide self-assembly mimics

“…These features are different from those of actual peptide self-assemblies. Recent molecular dynamics analyses suggest that the cross-␤ spine structures found in the sup35 peptide crystals represent a high-energy state and exhibit a significant twist as their structures are relaxed in computation (12).…”