In our laboratory, we utilize computational methods to study the properties and behavior of biomacromolecules and ligand-biomacromolecule complexes, and to aid in the design of small molecule ligands with desired binding properties for targeted receptors. Techniques used include quantum mechanical calculations, molecular dynamics and Monte Carlo simulation, and free energy perturbation methods. Computational methods complement experimental techniques and can enhance our understanding of biomacromolecular function.
Our current research interests are focused in several key areas. One area of research involves the use of computational methods to provide detailed molecular models for ligand-macromolecule recognition and binding processes. These studies can also suggest structural modifications for ligands (or biomacromolecules) that may enhance desired biological effects. For example, one active research project uses molecular modeling tools to help explain the molecular basis for the exquisitely tight binding of biotin to streptavidin. Collaborators are using site-directed mutagenesis, calorimetry, and x-ray crystallography to provide supporting data in these studies. Another project focuses on detailed study of cyclooxygenase structure-function relationships, reaction mechanism details, and inhibitor complexes.
A second area of research employs molecular modeling techniques, together with data from biochemical and biophysical studies, to generate three-dimensional models for proteins and protein-ligand complexes not currently tractable to direct experimental structural characterization. Most effort at present focuses on generation of 3D models for integral membrane receptor proteins that function in signal transduction pathways. One project involves an examination of structure-function relationships in bacterial chemotaxis receptors.
A final area of major research activity involves the development of new mathematical models and computer software to aid in modeling studies such as those outlined above. Much effort in recent years involves the development of methods to calculate free energy differences and solvation effects accurately in molecular dynamics simulations, as well as the development of algorithms for analysis and graphical display of simulation results.