The amino acid sequence of a protein encodes its three-dimensional
structure, and this structure manifests itself in biological function.
Using techniques that range from synthetic chemistry to cell biology, we
are illuminating in atomic detail both the chemical basis and the
biological purpose for protein structure and protein function. Our work now
focuses on the following problems.
Protein Function
We are revealing the molecular basis for the special
biological activities of two ribonucleases: onconase (which is toxic to
tumor cells) and angiogenin (which promotes neovascularization). In
addition, we are using nucleases to reveal fundamental insights into
enzymatic catalysis (including processivity) and protein - nucleic acid
interactions.
Protein Folding
Foldases catalyze the folding of other proteins. We are
designing and creating new protein and small-molecule foldases that
catalyze the formation of native disulfide bonds in vitro and in vivo.
Protein Stability
Collagen, the most abundant protein in animals, is a
simple protein with impressive stability. By using synthetic collagen
mimics, we are determining the contribution of hydrogen bonds and
stereoelectronic effects to this stability. Our mimics may provide new
materials for tissue welding and other medical procedures.
Protein - Protein Interactions
We are using novel genetic selections and
screens to identify molecules from combinatorial libraries that inhibit the
dimerization of HIV-1 protease or other proteins of therapeutic interest.
Our efforts are leading to insights into the relationship between amino
acid sequence and protein function (or dysfunction), as well as to the
creation of novel molecules with desirable properties.
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