Research Overview

Twenty amino acids make up the library from which natural polyamides – proteins – are synthesized. A typical small linear polypeptide might contain over 100 amino acid residues. In general, a polypeptide must fold into a single compact conformation to attain status as a functioning protein. The folding is directed by a myriad of noncovalent interactions: van der Waals, hydrophobic interactions, hydrogen bonding involving either side chain or main chain groups, aromatic stacking, and salt bridges. Given the enormous number of possible configurations that a polypeptide chain could sample, and the required delicate balancing act of the forces within a single macromolecule as well as between polypeptide and solvent, it is truly remarkable that protein folding is, most of the time, an extremely rapid and robust process.

Occasionally, though, proteins misfold, and misfolded proteins tend to aggregate. Misfolded and aggregated protein was once considered as interesting as yesterday’s trash – a bothersome byproduct of important and productive activities, to be disposed of and forgotten as quickly as possible. Today, however, interest in protein misfolding and aggregation has climbed dramatically for at least two reasons. First, therapeutic proteins are the fastest growing segment of the pharmaceutical industry, and aggregation poses substantial obstacles to the economic manufacture of safe, effective, and stable protein products. Second, protein aggregates are central players in a number of chronic degenerative diseases.

Our primary interest is in aggregation of a class of proteins known as amyloidogenic proteins. These proteins have been linked to the onset of the pathology associated with Alzheimer's disease, Huntington’s disease, and other neurodegenerative disease. Amyloidogenic proteins spontaneously misfold into insoluble aggregates with a β-sheet secondary structure and a fibrillar morphology. Considerable evidence has accumulated that links aggregation of specific proteins to cellular dysfunction and death in each of these diseases. Using a variety of biophysical techniques, we are characterizing the mechanism and kinetics of aggregation of disease-associated peptides, and the structure and morphology of the fibrillar aggregates. This detailed analysis at the molecular level is critical in order to establish the role of aggregation in the toxic response, and to develop rational strategies for therapeutic intervention. We are also exploring a variety of approaches for synthesizing compounds that interfere with aggregation. These compounds could potentially prevent the toxicity associated with amyloid proteins.