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Our research focuses on the biophysical chemistry and functional properties of proteins and nucleic acids. The problems we are interested in include the stability and structure of DNA, the structure of unfolded proteins and peptide models of these, the determinants of alpha helical stability, and design of new structures and functional agents using peptides. Techniques that we use in our research include NMR spectroscopy and structural analysis, chemical synthesis, kinetic and equilibrium optical, fluorescence and CD spectroscopy, and thermodynamics.

RESEARCH PROJECTS

1. Definition of the structure of unfolded peptides and proteins.

This research asks whether there is ordered structure in unfolded proteins. Currently held ideas about unfolded proteins are that they resemble random coils, with no favored structure at all. Our experiments on short chains of alanine and other amino acids revealed that there is a localized ordered structure present, predominantly the polyproline II (PPII) conformation. This conformation appears to be stabilized by water and is eliminated in the presence of nonaqueous solvents. Recently we have used spin labels and NMR to determine the dimensions of short unfolded chains in water. The results reveal a high population of PPII relative to other basins such as alpha or beta. Refining our knowledge of unfolded chains is important for providing information on early events in protein folding, and the propensity of the peptide backbone to acquire local structure. (SeeFast moving front in the field of Biology & Biochemistry)


2. Design and synthesis of novel antimicrobial agents based on host defense peptides.

The continuing need for antibiotics capable of overcoming resistance to current agents has stimulated research into compounds based on natural peptides used in host defense against infective agents by almost all organisms. Natural peptides rapidly kill a broad spectrum of bacteria and even viruses or fungi by permeabilizing their membranes. Most but not all these peptides are positively charged and amphipathic. Pursuing a multivalent strategy, our work has identified a new dendrimeric agent (RW)4D that is effective against gram positive and negative bacteria, including multi-drug resistant strains such as MRSA. A second series of designs attempts to replicate the pattern of amphipathic and charged groups in nonpeptidic compounds. These afford promising leads for small molecule antimicrobials that might be orally available.


3. New nanoscale assemblies created from coiled coil proteins.

One of the most prevalent protein-protein interfaces involves association between alpha helical coiled coils. Predicting the structure and geometry of these structures remains a challenge, since they can take on a variety of different forms. Thus coiled coils can differ in the number of helices that interact, whether the helices are parallel or antiparallel, homopolymeric or heteropolymeric, staggered or aligned. Even in this most intensively studied tertiary structure, there is a rich diversity of potential forms, and in many cases these can interconvert. Our strategy is to use stable higher order coiled coils to build novel assemblies such as surfaces that are responsive to metals, pH or salts. We have created branched coiled coils that can form regular geometric patterns for the first time.