August 2015


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"Diane St. Germain" <[log in to unmask]>
Wed, 19 Aug 2015 19:24:24 +0000
To: "[log in to unmask]" <[log in to unmask]>, "[log in to unmask]" <[log in to unmask]> cc: "[log in to unmask]" <[log in to unmask]>, COS Defense Announcement <[log in to unmask]>, Kerone Jones Wetter <[log in to unmask]>, Estela Blaisten-Barojas <[log in to unmask]>, Jason M Kinser <[log in to unmask]>
"Diane St. Germain" <[log in to unmask]>
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Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Christopher Lockhart

Program: PhD in Bioinformatics & Computational Biology

Date:   Monday August 31, 2015

Time:   1:30 PM
Place:  George Mason University
             Prince William Campus<>

             Occoquan Bldg., Room 327

Title: "All-Atom Explicit-Solvent Replica-Exchange Molecular

Dynamics Simulations of the Alzheimer's Disease A Monomer"
Committee Chair: Dr. Dmitri Klimov
Committee Members:  Dr. Iosif Vaisman, Dr. Saleet Jafri, Dr. Estela Blaisten-Barojas
A copy of the dissertation is available in the Mercer Library.  All are invited to attend the defense.
Using all-atom explicit-solvent replica-exchange molecular dynamics simulations, we have explored the changes in the conformational ensemble of the A monomer in various environments. In the simplest case, the A monomer in water forms mostly turn and random coil conformations. We show that the anti-aggregation agent ibuprofen, the zwitterionic DMPC lipid bilayer, and even the introduction of sequence truncation (to generate the A29-40 monomer) are capable of dramatically altering A conformations, resulting in stable helical structure present in the peptide's C-terminal. For comparison, the FDDNP biomarker and other sequence truncations (e.g., A23-40 and A28-40 monomers) do not exhibit a strong influence on A conformations. Thus, we conclude that there is an inherent helix propensity in the A C-terminal that can be revealed by certain environments.
More specifically, our work has demonstrated that the small ligands ibuprofen and FDDNP bind to the A monomer via the hydrophobic effect. Although ibuprofen promotes a change in A helical content, its low binding affinity and stabilization of the Asp23-Lys28 salt-bridge may partially explain its modest efficiency as an anti-aggregation agent. At the same time, the biomarker FDDNP induces minor change in the A conformational ensemble but binds with high affinity partially due to ligand clustering at hydrophobic binding sites. Although we argue that this benign effect on A is advantageous for in vivo neuroimaging of A fibrils, the high affinity binding of FDDNP to the A monomer raises the question of selectivity of this biomarker.
Finally, we have investigated the interactions of the A monomer with the zwitterionic DMPC bilayer. The bilayer causes a dramatic structural transition in A, resulting in stable C-terminal helix and formation of the Asp23-Lys28 salt-bridge. The central hydrophobic cluster and C-terminal of A not only govern binding to the bilayer but also penetrate into the bilayer hydrophobic core. As a result, A reduces the density of lipids in its binding footprint and indents the bilayer. Addition of calcium to these simulations results in a more profound effect, where lipid disorder and bilayer thinning by A are enhanced. These effects can be explained by a strengthening of A-bilayer interactions by calcium via enhanced electrostatic interactions between charged amino acids and lipid polar headgroups. Binding of A does not affect either water or calcium permeation into the bilayer. We propose that the limited scope of structural perturbations in the zwitterionic bilayer caused by the A monomer represents the molecular basis of its low cytotoxicity.