Research

Neuroscience is arguably the ultimate scientific challenge, and chemists must play a role in unraveling the great mystery of how the set of processes we call mind emerge from the activity of the organ we call the brain. We believe that chemists can have a large impact on this exciting field both by providing detailed insights into the ways that natural ligands and pharmaceuticals bind to receptors and by developing new chemistry-based tools to evaluate complex signaling pathways. In all our research, we seek to bring the tools and intellectual approach of physical organic chemistry to systems of biological importance.

The molecules of neuroscience are generally integral membrane proteins that have not succumbed to high resolution structural studies. Our strategy for gaining insight into their form and function has been to focus onto this key problem four of the most powerful techniques of modern science: organic synthesis, molecular biology, electrophysiology, and computer modeling.

A major tool for performing chemical-scale studies on receptors and channels has been the in vivo nonsense suppression methodology for incorporating unnatural amino acids into membrane proteins. Developed as part of an ongoing a collaboration between the Dougherty labs and the group of Henry Lester, Bren Professor of Biology at Caltech, this powerful tool allows us to incorporate an almost limitless array of unnatural amino acids into essentially all the key proteins of neuroscience. At the core of the technique is a combination of nontrivial organic synthesis and modern molecular biology to prepare novel aminoacyl tRNAs that deliver the unnatural amino acids to the ribosome. Details and some sense of the scope and generality of the method are described in the link titled Unnatural Amino Acid Methodology.

Most of the key proteins we study are ion channels, proteins that regulate the flow of ions across a membrane. The movement of ions across a membrane is identically equivalent to an electrical current, and, of course, it is now possible to measure very small electrical currents.  As such, electrophysiology provides a very powerful probe of ion channels. In fact, with the remarkable capabilities of the patch clamp, we can probe single channel molecules, providing unprecedented insights into the mechanisms of channel action. Importantly, electrophysiology provides a functional probe of a neuroreceptor.  We vary structure using the unnatural amino acid methodology and probe function through electrophysiology.  Such structure/function studies have been the foundation of physical organic chemistry since its inception, and we are now applying this approach to neurobiology.  Several examples of this approach and some background on neuroreceptors and channels are provided in the link titled Neuroreceptors and Drug-Receptor Interactions.

Computer modeling has always been a significant component of the Dougherty research program. We have employed the full range of computational methods: quantum mechanical methods including high level ab initio and DFT methods; molecular mechanics (modeling) from SPT studies of small molecule solvation to full MD runs on systems with over 120,000 atoms; RRKM calculations; tunneling calculations; data base searching and more. Our goal has always been to generate an interplay between theory and experiment - computations inspire new experiments and experiments inspire new computations. Over the years, roughly 50% of the experimentalists in the group have done some sort of nontrivial computation.

Our group pioneered the development of the cation-π interaction, a potent, general noncovalent binding force that stabilizes protein secondary structure and contributes to a wide range of drug-receptor interactions.  Using the unnatural amino acid methodology we established that cation-π interactions contribute to the binding of acetylcholine, serotonin, and g-aminobutyric acid (GABA) to their respective neuroreceptors (see Neuroreceptors and Drug-Receptor Interactions). A general introduction to the cation-π interaction and further examples are provided in the link titled The Cation-π Interaction.