Dr. DeGrado's research focuses on molecular design as an approach to understanding macromolecule structure and function.

Dr. DeGrado's primary research interest is in the de novo design of proteins, in which one attempts to design proteins from first principals. This approach critically tests his understanding of protein folding and function, while also laying the groundwork for the design of proteins with properties not precedented in nature. The de novo design of proteins has proven to be a useful approach for understanding the features in a protein sequence that cause them to fold into their unique three-dimensional structures. In addition, the DeGrado lab has recently been able to prepare a variety of functionally interesting proteins that bind redox-active cofactors, DNA, and transition metals.

A second area of interest is the design of small molecules that inhibit the interaction of cells with the extracellular matrix by binding to a class of membrane proteins known as integrins. Such compounds have potential as antithrombotic and anti-inflammatory drugs, depending on the integrin that is targeted.

A third area of interest is in the structure and function of membrane-active peptides. This laboratory has prepared peptides that act as ion channels, antibiotics and fusogenic agents. Tools used by the group in these projects include computer-aided molecular design, organic synthesis, peptide synthesis, protein expression, phage peptide libraries, NMR, and various forms of optical spectroscopy.

1. Yin, H., Slusky, J, S., Berger, B. W., Walters, R. S., Vilair, G., Litinov, R. I., Lear, J. D., Caputo, G. A., Bennett, J. S., DeGrado, W. F. (2007) Computational design of peptides that target transmembrane helices.  Science 315:1817-23.
2. Wade, H., Stayrook, S. E. and DeGrado, W. F. (2006) The structure of a designed diiron(III) protein: implications for cofactor stabilization and catalysis. Angew Chem Int Ed Engl 45:4951-4954.
3. Walters, R. F. and DeGrado, W. F. (2006). Helix-packing motifs in membrane proteins. Proc Natl Acad Sci USA 103:13658-13663.
4. Stouffer, A. L., Nanda, V., Lear, J. D., and DeGrado, W. F. (2005). Sequence determinants of a transmembrane proton channel: an inverse relationship between stability and function. J Mol Biol 347:169-179.
5. Cochran, F. V., Wu, S. P., Wang, W., Nanda, V., Saven, J. G., Therien, M. J., and DeGrado, W. F. (2005) Computational de novo design and characterization of a four-helix bundle protein that selectively binds a nonbiological cofactor. J Am Chem Soc 127:1346-1347.
6. Kaplan, J. and DeGrado, W. F. (2004) De novo design of catalytic proteins. Proc Natl Acad Sci USA 101:11566-11570.
7. Liu, D., Choi, S., Chen, B., Doerksen, R. J., Clements, D. J., Winkler, J. D., Klein, M. L., and DeGrado, W. F. (2004) Nontoxic membrane-active antimicrobial arylamide oligomers. Angew Chem Int Ed Engl 43:1158-1162.
8. Li, R., Mitra, N. Gratkowski, H., Vilaire, G., Litvinov, R., Nagasami, C., Weisel, J.W., Lear, J.D., DeGrado, W.F., Bennett, J.S. (2003) Activation of integrin alphaIIbbeta3 by modulation of transmembrane helix associations. Science. 300:795-798.