Seth Horne

Organic synthesis, bioorganic chemistry, biophysics, protein engineering

Research in the Horne lab is focused on the bioorganic chemistry of proteins. We apply peptides, proteins, and their unnatural analogues as (1) systems to study folding behavior and how to control it, (2) scaffolds for the development of therapeutics, and (3) bio-inspired materials. This interdisciplinary research program spans organic chemistry, biochemistry, biophysics, structural biology, and materials science.

From twenty amino acid building blocks and a simple condensation reaction, Nature produces proteins that perform the cellular functions underlying life. As chemists, we can modify the covalent structure of proteins and other biomolecules in ways limited only by our imagination and the synthetic ingenuity we apply in the implementation of our ideas. Synthetically modified peptides and proteins can teach us about natural biological processes and also act as scaffolds for the design of molecules that are inspired by nature but manifest new and interesting functions.

Short peptides and peptidomimetics with defined folds can mimic surfaces of natural proteins and block protein-protein interactions involved in disease. A key challenge in design of such species is controlling folded conformation. We are working to develop new methods to control peptide folding and create new protein-like objects with defined structure from short oligomers.

The design of molecular species that predictably arrange functional groups in space with sub-nm resolution over 100-1000 nm scales is a difficult problem. Nature is filled with examples of functional supramolecular assemblies, such as the multi-protein complex photosystem II. We are working to utilize biological recognition motifs in order to generate molecules capable of directed self-assembly to form supramolecular light harvesting chromophore arrays that mimic aspects of photosynthetic energy transduction.

In a protein, the sequence of amino acid side chains determines folded structure and function. Protein backbones can tolerate a surprising degree of chemical modification without compromising sequence-encoded folding. We are working to develop general strategies for the sequence-based mimicry of protein tertiary folds by analogues with unnatural backbones that are resistant to enzymatic degradation.