- Professor, Dept. of Biochemistry & Molecular Biology, University of Chicago
Department of Biochemistry and Molecular Biology
The University of Chicago
929 E. 57th Street, CIS W234
Chicago, IL 60637
Phone: 773 702 5073
Fax: 773 702 5073
The major goals of our research are to understand the molecular mechanisms underlying protein function at the atomic level and to exploit such knowledge to engineer proteins with novel shape and/or function.
Current research topics include:
(i) Molecular mechanisms of protein-protein interactions via engineering of small antibody mimics, “monobodies.” Specific binding is a fundamental aspect of protein function. This project was conceived on a concept that a binding site comprises a subset of surface residues that are strategically placed on a protein “scaffold”. We rationally design large combinatorial libraries of monobodies, which are built on a small scaffold of a fibronectin type III domain. We select monobodies with desired binding properties from the libraries and characterize them using biophysical tools. The current focus is on the role of conformational diversity in binding affinity and specificity. We are also applying this technology to structural genomics and cell biology.
(ii) Molecular mechanism of beta-sheet formation in peptide self-assembly. The formation of continuous beta-sheet is responsible for self-assembly of peptides (protein misfolding) associated with the so-called amyloid diseases (e.g. Alzheimer’s). However, the noncrystallin and insoluble nature of peptide self-assemblies makes their biophysical characterization extremely difficult. We overcome these fundamental difficulties by protein engineering. We have developed a model system that closely mimics the structure of peptide self-assembly using a unique, “single-layer” beta-sheet found in the OspA protein. These “peptide self-assembly mimics” allow us to apply standard biophysical tools to characterize the atomic structure and energetics of peptide self-assemblies in unprecedented resolution and precision. We also design nanomaterials using the self-assembly mimic system.