Catalytic methods for site-specific modification of natural proteins

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Zachary Ball from Rice University to investigate chemical reactions for protein modification. Proteins are incredibly large and complex molecules and selective alteration of proteins remains a daunting challenge. Nonetheless, chemically-modified proteins represent tantalizing opportunities. Applications of modified proteins include biomaterials for coatings or green energy and biological probes to understand, perturb, and inhibit biological pathways. Efforts under this award focus on developing new metal-mediated methods for protein modification. These novel methods allow the preparation of new sites with novel structures, reactivity, and biological properties. The research project is providing undergraduate students, graduate students, and postdoctoral fellows with training in synthetic organic and inorganic chemistry. In addition, these research participants are receiving training in techniques and modern analytical methods of protein chemistry. An integrated outreach program is introducing modern protein chemistry and analytical methods to local high school teachers and their students.In order to develop sequence-selective protein modification catalysts, this project employs rhodium(II) conjugates that enable modification of proteins, whether purified or in lysate, on the basis of molecular recognition. Catalytic modification provides a covalent readout for the presence and location of ligand binding, and thus allows identification of ligand-binding sites of "hit" compounds. The reactivity can also be harnessed to quantify inhibitors of weak, transient interactions that are difficult to study with existing methods. In a new direction, Chan-Lam coupling of boronate reagents allows copper-catalyzed modification of peptides and proteins, with unique sequence specificity. Unnatural chemical modification of metalloenzyme active sites has emerged as a powerful tool in metalloenzyme design. Boronate coupling promises to provide exciting new tools to build hybrid metalloproteins with new function and reactivity.