The presence of an abnormally expanded polyglutamine (polyGln) sequence in huntingtin protein ultimately results in beta-sheet-rich fibrillar aggregates, a hallmark of Huntington’s disease. Current challenges are to map out the pol- yGln aggregation pathway by identifying the various precursor structures and establish their pathological roles. We are using time-resolved small-angle neu- tron scattering (SANS) to probe the aggregates formed by peptides having the protein context of huntingtin exon 1 (HD protein) and with varying polyGln lengths. SANS is a particularly useful technique for following structural changes on the nanometer length-scale in solution. From the time-resolved scattering data, we obtain snapshots of the polyGln structures as the kinetics re- action ensues, which yields quantitative information on the size and shape of precursors and the internal structure of the resulting fibrils. Measured changes in the radius of gyration and mass per length illustrate multiple growth regimes with a transition from early aggregates to fibril elongation and association. Our SANS results on mature polyGln fibrils are consistent with the Perutz beta-he- lix structural model. This research is providing new insights into the pathway of polyGln aggregation and should later assist in determining the role that precur- sors play in neuronal toxicity. 1130-Plat Solid State NMR Studies Of Structural And Motional Complexity In Amyloid-Like Fibrils Of The Peptide GNNQQNY Patrick C.A. van der Wel 1,2 , Jo ´zef R. Lewandowski 2,3 , Robert G. Griffin 2 . 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Massachusetts Institute of Technology, Cambridge, MA, USA, 3 Universite ´ de Lyon, CNRS/ENS Lyon/ UCB-Lyon, Lyon, France. Solid state NMR allows the site-specific characterization of structure and dy- namics in a variety of immobilized biomolecules, and thus allows a unique structural view on amyloid fibrils. These fibrils are common to various human disorders and appear to share a number of characteristic features, both in terms of their structure and formation. In the hope of delineating the biophysical de- tails of the fibrillization process and the fibrils themselves, various groups have focused on the experimental and theoretical study of small peptide fragments of amyloid-forming proteins. One prominent system is the GNNQQNY 7-13 frag- ment of the yeast prion protein Sup35p, since it was found to form not just amyloid-like fibrils, but also seemingly amyloid-like microcrystals. X-ray dif- fraction based structures from the latter have inspired numerous theoretical analyses and generalizations regarding the biophysics and structures of amyloid fibrils. We have instead applied biological solid state NMR methods to characterize the GNNQQNY fibrillar aggregates. Magic angle spinning (MAS) solid state NMR was used for various structural measurements, aimed at both the intra- molecular as well as intermolecular structural motifs of the fibrils (as well as the crystalline aggregates). Our studies have revealed a remarkable com- plexity in these fibrils, despite the relatively small size of the peptide build- ing blocks. This is in marked contrast with the rigid and homogeneous nature of the crystalline structures, as revealed by X-ray crystallography and solid state NMR. These observations provide further insights into the structure of the fibrils of this peptide model system and should also be of importance as input to numerous theoretical studies that rely on the crystal structure data. 1131-Plat Computational Study of Assembly and Toxicity Inhibition of Amyloid Beta-Protein and Its Arctic Mutant Brigita Urbanc 1 , Gal Bitan 2 , Luis Cruz 1 , Alfonso Lam 3 , David Teplow 2 . 1 Drexel University, Philadelphia, PA, USA, 2 University of California, Los Angeles, Los Angeles, CA, USA, 3 Boston University, Boston, MA, USA. Amyloid b-protein (Ab) exists in two main alloforms, Ab40 and Ab42, of which Ab42 is linked particularly strongly to Alzheimer’s disease (AD). Prior com- putational work demonstrated that the ab initio discrete molecular dynamics approach with an intermediate-resolution protein model captures biologically relevant differences between Ab40 and Ab42 folding and oligomerization. In the present work we apply the same approach to explore the relationship between the structure and toxicity. Assuming that Ab42 oligomers are more toxic than oligomers formed by Ab40, our structural analysis indicates that the solvent accessible surface area (SASA) in the N-terminal region of Ab42 oligomers is significantly higher than that of Ab40 oligomers. We then investi- gate effects of the C-terminal fragment (CTF), which was shown to attenuate Ab42 oligomer toxicity in a cell culture, on Ab42 oligomerization. Our results indicate that CTFs associate with Ab42 to form heterooligomers, consistent with quasielastic light scattering data. We show that the presence of CTFs sig- nificantly reduces SASA in the N- terminal region of Ab42 compared to the same region in Ab42 oligomers formed in the absence of CTFs. We further explore folding and oligomer formation of the Arctic mutants, [E22G]Ab40 and [E22G]Ab42, associated with a familial form of AD. Our re- sults demonstrate that the substitution E22G disrupts the folding structure and oligomerization pathways of both Arctic mutants and results in increased SASA at the N-terminus of the Arctic Ab40 mutant. These findings suggest that Ab oligomer neurotoxicity might be directly or indirectly associated with the degree of solvent exposure of the N-terminal region of Ab. 1132-Plat Discrete Molecular Dynamics simulations on hexameric amyloid-b (1-40) and (1-42) models Sijung Yun, H. Robert Guy. National Cancer Institute, Bethesda, MD, USA. Aggregation of amyloid-b peptides (Ab) may play a pivotal role in neurotox- icity of Alzheimer’s disease. Two major alloforms of Ab are the 40-residue long Ab40 and the 42-residue long Ab42. Though Ab42 has only two more res- idues at the end of C-terminus, Ab40 and Ab42 show different characteristics in early aggregation: Ab40 aggregates to exist from monomers up to tetramers while Ab42 exists from monomers to hexamers, dodecamers, or even octade- camers. However, the molecular mechanism of the different aggregation between Ab40 and Ab42 is not clearly understood since their oligomeric struc- tures are not available from experiments due to their meta-stable characteris- tics. Here, we simulated nine hexameric Ab40 and nine hexameric Ab42 models with Discrete Molecular Dynamics (Discrete MD). The hydrophobic core of these models is a six-stranded b-barrel formed by residues 30-40 that has three-fold symmetry about its axis. This core is shielded from water by res- idues 1-28. The models differ by the relative positions of the core b strands, and whether the other segments surrounding the core contain a helices or b-strands. The potential energy of Ab40 measured by Miyazawa-Jernigan interaction matrix were considerably lower than the potential energy of Ab42 in all of 18 models tested, probably because more hydrophobic residues are exposed to water in theAb42 models. In two of nine models of Ab42, dangling hydro- phobic b-strands emerged on the surface. This implies that the association of these hexamers may be possible, which could lead to the formation of larger assemblies. Platform X: Exploring the Unfolded State of Peptide & Proteins 1133-Plat Concentration Dependent Instability of ß-sheet aggregates of Ac-(AAKA) 4NH2 in solution Thomas J. Measey, Melinda Bendon, Reinhard Schweitzer-Stenner. Drexel University, Philadelphia, PA, USA. The amphiphatic polyalanine peptide, Ac-(AAKA)4-NH2, has recently been shown to aggregate into a hydrogel at high chloride concentration or alkaline pH. It forms soluble ß-sheet type aggregates at neutral pH and centimolar con- centrations. In order to further characterize the transition from the monomeric to the aggregated state, we measured the far UV-ECD spectrum at different concentrations between 35 - 700 mM. At very low concentration (i.e. 0.05 mg/mL or 35 mM) the observed spectrum is indicative of a stable mixture of right handed a-helical and ß-strand (sheet) conformations. At higher concentra- tions (> 1 mM) we observed a spectrum reflecting a very stable ß-sheet aggre- gate. However, at concentrations between 70 - 700 mM the peptide shows a very strange, and totally unexpected, behavior. Upon dissolving it in solution, a sta- tistical coil-like mixture comprising polyproline II (PPII), a-helical and ß-sheet-like conformations is formed. Subsequently, most of the ß-sheet frac- tion decays into a conformation which exhibits a PPII-type ECD spectrum on a time scale of 104-105 s. The kinetics of the process follows a power law at low concentrations and becomes mono-exponential at higher concentration. Generally, the relaxation slows down with increasing peptide concentration until the ß-sheet becomes stable on the time scale of our experiments (<105 s). We hypothesize that aggregation involves multiple steps with the formation of a rather unstable ß-sheet as the first step. The second step involves the forma- tion of stable fibers. This step competes with the formation of collagen like coil-coil state, rather, which is known to exhibit a PPII-like ECD spectrum. 1134-Plat Characterization of the Disordered Regulatory Domain from Calcineurin Trevor P. Creamer, Veronique M. Chellgren, Anne E. Jensen, Terrence E. Lester. University of Kentucky, Lexington, KY, USA. Calcineurin (CaN) is a highly-conserved, ubiquitous Ser/Thr phosphotase that plays vital roles in memory development and retention, cardiac growth, and Monday, March 2, 2009 219a