Center for Bioinformatics at KU

As part of our public Seminar Series
http://bioinformatics.ku.edu/seminars

August 27, Thu 2009
1:00 pm, MRB 200 Conference Room

Dr. Yogita Mantri

University of Indiana

Computational Modeling of Transition Metals in Medicinal Chemistry: Modeling the Copper-bound Amyloid-β peptide of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by insoluble, fibrillous plaques in brain tissues consisting of Amyloid- β peptides (Aβ ). High concentrations of redox-active metals such as copper have been found in the vicinity of the plaques, and the surrounding tissues show evidence of oxidative damage. These facts combined have led to a proposed mechanism of pathogenecity in AD that involves the formation of an Aβ -Cu complex which catalytically activates dioxygen to generate hydrogen peroxide. One of the first steps in studying such a catalytic reaction with the goal of developing anti-AD therapies, is an atomistic description of the Aβ -Cu complex. Experimental data on this complex is incomplete and conflicting. Our approach to this problem was to use the relative copper-binding free energies of a series of Aβ -Cu complexes with different ligands, in order to predict the most plausible ligands around the copper center. To this end, we employed a novel combination of high-level quantum mechanical methods to describe the CuII center, coupled with classical molecular dynamics simulations to account for the flexibility of Aβ . The details of this methodology and the implications of the results will be discussed in this presentation.