One quarter of all the proteins in the human genome are membrane proteins. More importantly, membrane proteins constitute more than half of all known drug targets. Our laboratory is studying the structure and folding of proteins and peptides in membranes through experiments in which we design and engineer peptides that fold in membranes, peptides that interact with membrane proteins, and peptides that mimic the structure of membrane proteins. The laboratory's research is focused on several key areas:

Combinatorial Design of Peptide Pore-formers

In a combinatorial chemistry experiment, a large collection of peptides, with as many as a million members, is produced and the library is screened for those members that have a desired property. This is an extremely powerful technique, and we are using it to design peptides that assemble in membranes into membrane-spanning pores or channels. Using the pore-forming peptides we have discovered with this technology, we are engineering novel peptide antibiotics, peptide biosensors and drug delivery vehicles.

Combinatorial Design of Receptor Modulators

We are also using combinatorial chemistry and high throughput screening to design membrane-spanning peptides that interact with important receptor proteins and modulate their biological activity. Peptide drugs that interact with a receptor can modulate its biological activity by altering its structure or dynamics. Our current protein targets are G-protein coupled receptors and receptor tyrosine kinases.

Assembly of Peptide Sheets in Membranes

Understanding the fundamental principles of folding, structure and function of membrane proteins is essential to the laboratory's research. Toward this goal, we are designing model peptides to assemble into specific types of structures in membranes, and we are characterizing their structure and folding using biophysical methods. The information obtained in these experiments helps us to design the combinatorial libraries used in the high-throughput screening experiments.

Identification of Membrane Proteins in Genome Databases

With the completion of the sequencing of the human genome, along with hundreds of genomes from other organisms, the task of assigning structure and function to millions of protein sequences has become essential. The laboratory is using bioinformatics and computer programming to identify and characterize putative membrane proteins in genomes. Specifically, we are working to accurately identify the outer membrane proteins of pathogenic Gram negative bacteria, such as those that cause food poisoning, cholera, whooping cough, plague and meningitis.