People - [ Faculty ]
The Effects of Mutations on Carboxylesterases
Carboxylesterases are a family of enzymes that catalyze the hydrolysis of ester bonds. These enzymes are the primary detoxification mechanism for many xenobiotic compounds, and they have been implicated in the control of cholesterol levels. We are interested in understanding how mutations of these enzymes affect their efficiency. The goal is to understand how subpopulations may be at greater risk from pesticide exposure or may have a greater risk of heart disease.
We have been using molecular dynamics simulations to study how site specific mutations change the interactions between a bacterial model carboxylesterases and a substrate. We then correlate our calculations with the experimentally determined effects of the mutations.
Reactivators to Counter Nerve Agent Exposure
Potential exposure to nerve agents is both a significant risk for military personnel and a potential risk among the civilian population. The cause of the primary toxicity of the nerve agents is known - phosphonlylation of the enzyme acetylcholinesterase. The current treatment for nerve agent exposure is to administer a cholinergic antagonist and to give a reactivator to reverse the enzyme phosphonlylation.
However, the current reactivators are not broad enough in their effectiveness. We are currently using molecular dynamics and electronic structure theory to model the molecular mechanism by which oxime reactivators work. The goal of this research is to provide the information needed to design new reactivators that are more effective against a broader range of threats.
Mechanism of Nitration Reactions
Electrophilic aromatic substitutions, in particular electrophilic aromatic nitrations, are considered classic organic chemistry reactions. And although the basic mechanism was worked out in the 1960's, the details of the mechanism still remain under debate. Recently, we have used CCSD(T) and DFT calculations to reexamine the potential energy surface for the reaction of the nitronium ion with benzenes.
This work has lead to a consistent picture of how the nitration reaction proceeds in benzene through p and s intermediates. A future area of research is to study substituted benzenes to see if the same basic mechanism can be used to explain the known regioselectivity of nitration reactions.
Properties of Molecules in Solutions
Quantum chemistry has defined much of the way people think about the field of chemistry. From the molecular orbital to the potential energy surface, many of our basic chemical concepts derive from quantum chemistry. In addition, in some cases it is now possible computationally to exceed the accuracy of experiments for ground-state properties of small molecules in the gas phase. However, if we model a solute surrounded by solvent molecules, the quality of the calculated results drops dramatically. Therefore, one focus of my group's research is to develop new methods for calculating properties of solvated molecules within the framework of high-accuracy electronic structure theory.