Computer Science Seminar Series
Computer Simulation of Biomacromolecules
3:00 pm Wednesday, October 14, 2009
Weir Hall, Room 235
Dr. Randy M. Wadkins
Abstract:
My group is studying carboxylesterases (CEs), which are ubiquitous enzymes responsible for the detoxification of xenobiotics. CEs may also be used to protect against exposure to the organophosphate nerve agents that target the related enzyme acetylcholinesterase (AChE). AChE enzymes react in a stoichiometric fashion with the organophosphate, resulting in the accumulation of acetylcholine in the synapses and leading to death from respiratory failure. CEs, in contrast to AcChE, can convert organophosphates to metabolized products. An exciting prospect is the engineering of CEs that can catalytically inactivate organophosphates. Such engineering, however, will require a more thorough understanding of the relationship between CE structure, substrate selectivity, and catalytic activity. The specificity of CEs for a particular substrate or inhibitor depends on the enzyme's molecular structure, and importantly, on the dynamics of conformational substructures present within an enzyme when a substrate is bound. Structural dynamics of CEs, therefore, have critical roles in drug detoxification and can be studied by a combination of experimental and theoretical techniques. The goals of our studies are then to study the dynamics of CEs by molecular dynamics simulations and to compare the fluctuations in molecular structure of these enzymes with their substrate conversion activities. We will also present a general overview of general computational experiments on biomacromolecules.
Bio:
Dr. Randy M. Wadkins has been involved with antitumor drug development since the start of his graduate work. He graduated in 1986 with a B.S. in Chemistry from the University of Mississippi. He stayed on at Ole Miss to do his graduate training, where he examined the mechanism of DNA binding by the antitumor drug amsacrine. He received his Ph.D. in Chemistry in 1990 and then accepted a post-doctoral training position at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany. At the Max Planck, he was the first to identify that the potent antitumor drug actinomycin D was able to specifically interact with single-stranded DNA. This finding has been widely cited by researchers pursuing anti-HIV drugs since HIV infection proceeds through a single-stranded DNA intermediate step that has been shown to be inhibited by actinomycin D. Dr. Wadkins then moved to St. Jude Children's Research Hospital in Memphis where he worked for over 3 years on drug resistance in cancer cells and the development of drugs to circumvent resistance. His interests in novel techniques for detection of cancer took him to the Naval Research Laboratory in Washington, DC, where for two years he learned to construct analytical biosensors. He is currently interested in adapting the biosensor technology for detection of patient response to antitumor chemotherapy. In 1996, he accepted an Assistant Member position at the Cancer Therapy and Research Center in San Antonio, TX. There, he worked closely with Dr. Daniel D. Von Hoff (past President of the American Association for Cancer Research) and Drs. Monroe Wall and M.C. Wani (discoverers of the antitumor drugs taxol and camptothecin). Dr. Wadkins joined the Johns Hopkins Oncology Center in October of 1999 as an Assistant Professor. He returned to the University of Mississippi as an Assistant Professor of Chemistry and Biochemistry in 2003, and was promoted to Associate Professor in 2009. He continues to explore the interaction of antitumor drugs with their target molecules.