Bulletin of the American Physical Society
APS March Meeting 2013
Volume 58, Number 1
Monday–Friday, March 18–22, 2013; Baltimore, Maryland
Session J43: Focus Session: Protein Misfolding and Aggregation I |
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Sponsoring Units: DCP DBIO Chair: Elsa Yan, Yale University Room: Hilton Baltimore Holiday Ballroom 2 |
Tuesday, March 19, 2013 2:30PM - 3:06PM |
J43.00001: Role of sequence and membrane composition in structure of transmembrane domain of Amyloid Precursor Protein Invited Speaker: John Straub Aggregation of proteins of known sequence is linked to a variety of neurodegenerative disorders. The amyloid $\beta $ (A$\beta )$ protein associated with Alzheimer's Disease (AD) is derived from cleavage of the 99 amino acid C-terminal fragment of Amyloid Precursor Protein (APP-C99) by $\gamma $-secretase. Certain familial mutations of APP-C99 have been shown to lead to altered production of A$\beta $ protein and the early onset of AD. We describe simulation studies exploring the structure of APP-C99 in micelle and membrane environments. Our studies explore how changes in sequence and membrane composition influence (1) the structure of monomeric APP-C99 and (2) APP-C99 homodimer structure and stability. Comparison of simulation results with recent NMR studies of APP-C99 monomers and dimers in micelle and bicelle environments provide insight into how critical aspects of APP-C99 structure and dimerization correlate with secretase processing, an essential component of the A$\beta $ protein aggregation pathway and AD. [Preview Abstract] |
Tuesday, March 19, 2013 3:06PM - 3:42PM |
J43.00002: Spontaneous Formation of Oligomers and Fibrils in Large-Scale Molecular Dynamics Simulations of A-beta Peptides Invited Speaker: Carol Hall Protein aggregation is associated with serious and eventually-fatal neurodegenerative diseases including Alzheimer's and Parkinson's. While atomic resolution molecular dynamics simulations have been useful in this regard, they are limited to examination of either oligomer formation by a small number of peptides or analysis of the stability of a moderate number of peptides placed in trial or known experimental structures. We describe large scale intermediate-resolution molecular dynamics simulations of the spontaneous formation of fibrils by systems containing large numbers ( 48) of peptides including A-beta (16-22), and A-beta ( 17-42) peptides. We trace out the aggregation process from an initial configuration of random coils to proto-filaments with cross-$\beta $ structures and demonstrate how kinetics dictates the structural details of the fully formed fibril. Fibrillization kinetics depends strongly on the temperature. Nucleation and templated growth via monomer addition occur at and near a transition temperature above which fibrils are unlikely to form. Oligomeric merging and structural rearrangement are observed at lower temperatures. [Preview Abstract] |
Tuesday, March 19, 2013 3:42PM - 4:18PM |
J43.00003: Exploring the Free Energy and Conformational Landscape of Peptides Upon Aggregation and Amyloid Formation Invited Speaker: Roland Winter Using various physical-chemical tools and perturbation parameters, the effects of temperature, pressure as well as lipid interfaces and confining geometries on the various stages of the aggregation and fibrillation reaction of amyloidogenic peptides have been studied. First we show data on the experimentally derived static structure factor obtained for the protein insulin which has been analyzed with a statistical mechanical model based on the DLVO potential. The data reveal that the protein self-assembles into equilibrium clusters already at low concentrations in the pre-nucleation phase. Then, mechanistic details about the nucleation process and concurrent aggregation pathways of insulin and more disease related amyloidogenic peptides, such as IAPP and PrP, and the differential stability of the aggregate structures formed are discussed. Also solvational perturbations, accomplished by the addition of various salts and cosolvents have been explored. They exert pronounced and diversified effects on the unfolding, non-native assembly and fibril formation, which ultimately manifest in morphological variations of mature aggregates and fibrils. Finally, the presence of lipid interfaces and soft-matter confinement will be discussed, which drastically change the aggregation pathway as well as the kinetics of peptide aggregation. Using various model membrane systems, the influence of different membrane characteristics on the lipid-protein interaction has been revealed. [Preview Abstract] |
Tuesday, March 19, 2013 4:18PM - 4:54PM |
J43.00004: Chaotic (``Non-Pathway'') Aggregation of $\beta $-Amyloid Congener Peptides Invited Speaker: Stephen C. Meredith We compared A$\beta_{21-30}$ and A$\beta _{16-34}$, with or without N-terminal Cys or cyclization. All A$\beta_{21-30}$ variants were monomeric and unstructured. In contrast, A$\beta_{16-34}$ and Cys-A$\beta_{16-34}$ formed fibrils -- the latter more rapidly, due to disulfide bond formation. NMR showed no long-range nOes. In serial NOESYs, after changing pH (3 to 7.4) to initiate aggregation, some chemical shifts did not change, while others changed dramatically. In addition, although signals diminished globally with aggregation, the decay rates for individual peaks varied over $\sim$ 4-fold range. We attribute selective signal loss to conformational constraints restricting local tumbling and/or static structural heterogeneity. Signal decays for A$\beta_{16-34}$ and Cys-A$\beta_{16-34}$ differed in three ways: 1) Decay rates for Cys-A$\beta_{16-34}$ \textgreater\ A$\beta_{16-34}$; 2) variances for rate constants of Cys-A$\beta_{16-34}$ \textless\ A$\beta_{16-34}$ across replicate experiments; 3) smaller variances of rate constants within single experiments for Cys-A$\beta_{16-34}$ than A$\beta_{16-34}$. These results indicate both acceleration and ordering of aggregation by the disulfide bond in Cys-A$\beta_{16-34}$ compared to which aggregation of A$\beta_{16-34}$ was chaotic and disordered. Our results highlight several essential differences between protein folding and unfolded protein aggregation.\\[4pt] In collaboration with Laura M. Luther, Joshua T.B. Williams, Andrew J. Hawk, and Joseph R. Sachleben, The University of Chicago. [Preview Abstract] |
Tuesday, March 19, 2013 4:54PM - 5:30PM |
J43.00005: Challenges for understanding protein aggregation through computer simulations Invited Speaker: Normand Mousseau The first computer simulations of protein aggregation were performed a little more than decade ago. Over the years, the community of computer biochemists, chemists and physicists has grown considerably and the simulations becoming more realistic and often closer to experiments, due both to a better understanding of the onset of aggregation and to ever more powerful computers. In view of this expansion both in terms of papers and system size, what have been the real contribution of these simulations to our understanding of amyloid diseases? In this talk, I will present a personal view of the progress that has been accomplished over the last decade. I will aslo discuss some of the challenges that must still be overcome for computer simulations to move to the next level of contributions to this fundamental problem. [Preview Abstract] |
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