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BITS2007 Meeting
BITS2007 Meeting



26-28 April 2007 Napoli, Italy

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Molecular dynamics analyses of peptides forming amyloid-like fibrils
 
Motivation
The insurgence of severe neurodegenerative disease is frequently associated with
insoluble amyloid-like fibrils . The structural characterization of these fibrils has
long been hampered by the very low solubility and by the non-crystalline nature of
these aggregates. Major advances in this field have been recently accomplished by the
use of model peptides, whose solid aggregates exhibit most of the features of amyloid
fibrils. 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. The high resolution structure of the peptide offered an
atomic detailed model, denoted as cross-beta spine steric zipper, for amyloid-like
fibrils (Nelson, R., Sawaya, M.R., Balbirnie, M., Madsen, A.O., Riekel, C., Grothe,
R., Eisenberg, D. (2005) Nature 435, 773-8). In order to obtain further insights into
the structure determinants of amyloid fiber structure and formation, we have
undertaken molecular dynamics (MD) simulations on a variety of different models
arranged in a cross-beta spine structure

Methods
The starting coordinates for the MD simulations were derived from the crystal
structure of the peptide GNNQQNY. For simulation on polyglutamine systems, the
starting models were generated by molecular modelling using the structure of GNNQQNY
as template. MD simulations were performed with the GROMACS software package. Models
were immersed in rectangular or cubic boxes filled with water molecules. An extensive
analysis of GNNQQNY dynamics was performed by using replica exchange MD (REMD), an
advanced methodology for enhancing conformational sampling.

Results
The MD simulations of several GNNQQNY assemblies of different sizes indicate that the
aggregates are endowed with a remarkable stability. Our data also indicate that these
assemblies can assume twisted  beta-sheeted structures. As a consequence, the
occurrence of steric zipper interactions is compatible with both flat and twisted
beta-sheets. This result is in line with several literature reports suggesting
twisted beta-sheet structures as a basic motif of amyloid fibrils. The evolution of
pairs of sheets separated by a wet interface during the simulation has additionally
provided interesting information on the structure of larger aggregates (Esposito, L,
Pedone, C e Vitagliano, L. (2006). Proc. Natl. Acad. Sci. USA 103, 11533-8). Further
studies carried out by using REMD approaches have provided interesting clues on the
structural properties of the intermediate states along the fiber formation pathway.
Our findings are in line with the concentration dependent lag phase growth of GNNQQNY
fibers experimentally observed.
Finally, MD simulations were also used to investigate the structural compatibility of
polyglutamine fragments, associated with the occurrence of several neurodegenerative
diseases, with the steric zipper model. MD simulations have been carried out on a
variety of models (parallel and antiparallel pairs of sheets) with different sizes
and various aggregation levels. Our simulations, carried out over a wide range of
temperatures, 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
polyglutamine models. 
Simulations carried out at high temperatures (450-500 K) also show that the steric
zipper motif is reversibly destroyed. This provides a clear indication on the
structural determinants that regulate its formation. On this basis, a mechanism that
explains the nucleation-dependent process of polyglutamine fiber formation is
proposed.
 
Id: 105
Place: Napoli, Italy
Centro Congressi "Federico II"
Via Partenope 36
Napoli
Starting date:
28-Apr-2007   12:50
Duration: 20'
Contribution type: Oral
Primary Authors: VITAGLIANO, Luigi (Istituto di Biostrutture e Bioimmagini, C.N.R., Napoli)
Co-Authors: PALADINO, Antonella (Istituto di Biostrutture e Bioimmagini, C.N.R., Napoli)
PEDONE, Carlo (Istituto di Biostrutture e Bioimmagini, C.N.R., Napoli)
ESPOSITO, Luciana (Istituto di Biostrutture e Bioimmagini, C.N.R., Napoli)
Presenters: VITAGLIANO, Luigi
 
Included in session: Session 7: Structural biology and drug design
Included in track: Structural biology and drug design
 




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