The ASPIRE Path in Molecular Medicine

My research project focuses on incorporating sparse experimental restraints into a de novo protein structure prediction algorithm: BCL::Fold developed at Vanderbilt University. Currently we know the structure of a limited set of membrane proteins. They are too large for NMR spectroscopy and do not crystallize for X-ray crystallography. Over 50% of all therapeutics target membrane proteins because of the function they play in cell signaling pathways. A solid understanding of membrane protein structure is critical to improved drug design and optimization. To systematically test each possible conformation of a particular protein in silico would take more time than the universe is old, yet nature folds proteins in a matter of seconds. The final protein shape is thought to be near the state of lowest free energy. The problem of protein structure prediction is transformed into a search for all possible conformations of an amino acid sequence on the free energy landscape for the conformation of lowest energy. Currently, no practical method for finding the conformation with the lowest free energy exists. Because of this limitation, I incorporated Small Angle X-Ray Scattering (SAXS) restraints into BCL::Fold. I plan on combining SAXS with NMR and Cryo-EM to generate native like protein models in Silico.

My clinical interest is in Schizophrenia and its associated neuropharmacology. A comprehensive understanding of the molecular basis of this disease has been elusive. In fact, most of the initial typical antipsychotics were discovered by chance. I hope to use my clinical experience to learn how patients of different backgrounds respond to different antipsychotic medications. I would like to understand why certain drugs are more effective than other drugs during treatment and how we can optimize the therapeutic effect while minimizing the side effects of antipsychotic medications. To answer these fundamental questions, I will identify key protein receptors involved in the etiology of schizophrenia and predict their structure using a hybrid method approach combining SAXS, NMR, Cryo-EM and BCL::Fold.