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<http://www.gmu.edu/resources/welcome/Directions-to-GMU.html>
Occoquan Bldg., Room 327
Title: "All-Atom Explicit-Solvent Replica-Exchange Molecular
Dynamics Simulations of the Alzheimer's Disease Aâ 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 Aâ monomer in various environments. In the simplest case, the Aâ 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 Aâ29-40 monomer) are capable of dramatically altering Aâ conformations, resulting in stable helical structure present in the peptide's C-terminal. For comparison, the FDDNP biomarker and other sequence truncations (e.g., Aâ23-40 and Aâ28-40 monomers) do not exhibit a strong influence on Aâ conformations. Thus, we conclude that there is an inherent helix propensity in the Aâ 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 Aâ monomer via the hydrophobic effect. Although ibuprofen promotes a change in Aâ 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 Aâ conformational ensemble but binds with high affinity partially due to ligand clustering at hydrophobic binding sites. Although we argue that this benign effect on Aâ is advantageous for in vivo neuroimaging of Aâ fibrils, the high affinity binding of FDDNP to the Aâ monomer raises the question of selectivity of this biomarker.
Finally, we have investigated the interactions of the Aâ monomer with the zwitterionic DMPC bilayer. The bilayer causes a dramatic structural transition in Aâ, resulting in stable C-terminal helix and formation of the Asp23-Lys28 salt-bridge. The central hydrophobic cluster and C-terminal of Aâ not only govern binding to the bilayer but also penetrate into the bilayer hydrophobic core. As a result, Aâ 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 Aâ are enhanced. These effects can be explained by a strengthening of Aâ-bilayer interactions by calcium via enhanced electrostatic interactions between charged amino acids and lipid polar headgroups. Binding of Aâ 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 Aâ monomer represents the molecular basis of its low cytotoxicity.