Effect of polarization and charge on biological halogen bonds

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In this award from the Chemistry of Life Processes Program in the Chemistry Division, Drs. Pui S. Ho and Anthony K. Rappe, from Colorado State University, will characterize the geometry-energy relationships of, and derive from these relationships methods to model halogen bonds (X-bonds) accurately in biological systems. X-bonds are important non-covalent interactions in defining the specificity of many inhibitors to their protein targets. The hypothesis is that X-bonds are underutilized in inhibitor design, because of our incomplete understanding for how their geometries define their energies. The long-term goal of the research is to develop a set of potential energy functions to describe X-bonds, starting with extensive characterization of the geometry-energy relationships for the interactions in biological molecules. To accomplish these goals, the researchers will compare the effects of polarization of the halogen X-bond donor and the charge of the X-bond acceptor on the structure and energies of X-bonds in DNA junctions in T4 lysozyme. They will also study how these physicochemical effects contribute to ligand binding using a set of lysozyme constructs with artificial pockets engineered at various sites in the protein. Finally, they will develop quantum chemical methods to model the experimental structure-energy relationships. The experimental and quantum mechanical results will eventually be integrated to develop new potential energy functions for biological X-bonds that can be incorporated into molecular mechanics force fields that are used in biomolecular modeling.The outcomes of this research project are likely to impact the computer-aided design of new classes of drugs. Efforts will also be made to integrate research with science education, by using scientific problems derived from the research component to guide class projects related to the basic principles taught in a Physical Biochemistry course. Finally, this project, which integrates experimental and theoretical methods to characterize unique molecular interactions, is expected to continue to provide a diverse group of postdoctoral trainees, graduate and undergraduate students (including women and students of diverse backgrounds) with broad training in the areas of structural biology and biological chemistry.