Despite much attention, we still do not fully understand how the chemistry of a protein specifies its active structure. Our lab therefore dissects proteins chemically to identify the molecular features that govern folding. We are particularly interested in the chemistry that drives the general propensity of proteins to misfold.
Despite decades of research, our understanding of protein chemistry is insufficient to predict the structure of a protein from first principles. We are on the hunt for missing features of protein chemistry that could contribute to structure. Based on predictive calculations and/or inventories of the chemical interactions in known protein structures, we can identify groups or moieties that are likely to be engaged in unappreciated interactions that could govern structure. From there, we can build synthetic models of proteins that allow us to dissect these contributions atom-by-atom. We have previously applied this approach to identify previously unappreciated interactions involving backbone carbonyl groups that contribute to secondary structure formation. In addition to identifying the chemical interactions that shape native protein structures, we are particularly interested in the chemistry that governs protein misfolding. Misfolded proteins, regardless of sequence, consistently become enriched in beta-sheet secondary structure, but the chemistry responsible for this general disposition remains unclear.
Students and scientists working on these problems in our lab use techniques and approaches from organic chemistry, chemical biology, and biophysics, including organic synthesis, peptide synthesis, mass spectrometry, spectroscopy, calorimetry, NMR, X-ray crystallography, computational chemistry, and structural bioinformatics.