Department of Biochemistry Box 357350 University of Washington Seattle, WA 98195
 



 
 
 

      
Valerie Daggett          

Adjunct Professor of Biochemistry
Professor of Medicinal Chemistry

206.685.7420 V
206.685.3252 F
daggett@u.washington.edu

 

Research

Our goal is to perform realistic molecular modeling studies relating to protein stability, dynamics, function, and folding. Protein folding is one of the fundamental unsolved problems in molecular biology. A protein must assume a stable and precisely ordered conformation to perform its biological function properly. Although much is known of the structural details of the native folded conformation of proteins, very little is known about the actual folding process. An understanding of protein folding has important implications for all biological processes, including protein degradation, protein translocation, aging, and human diseases, including cancer and amyloid diseases. The solution to the protein folding problem also has applications in the human genome project and biotechnology. Given that protein folding is of such widespread importance to human health and the fact that experimental approaches only provide limited amounts of information on the structural transitions and interactions occurring during protein folding, we are using computer simulation methods in an attempt to delineate the important forces acting during this process. We have also become involved in biomaterial design, making use of what we have learned in our structural, dynamics, and folding studies of well-studied globular proteins. In addition, we are applying our expertise to a variety of proteins that experience conformational changes in vivo and lead to disease (for example, the prion protein, transthyretin and Ab, the peptide implicated in Alzheimer's disease). Finally, while we are application oriented, we do a good deal of methods and force field development.

 Selected Publications

Armen, R.S., DeMarco, M.L., Alonso, D.O.V. and V. Daggett, Pauling and Corey's a-pleated sheet structure may define the prefibrillar amyloidogenic intermediate in amyloid disease Proceedings of the National Academy of Sciences USA, 101, 11622-11627, 2004. [PDF]

Editorial on this paper in Nature. [PDF]
Editorial on this paper in Science. [PDF]

DeMarco, M.L., Alonso, D.O.V. and V. Daggett, Diffusing and colliding: The atomic level folding/unfolding pathway of a small helical protein, Journal of Molecular Biology, 341, 1109-1124, 2004. [PDF]

Beck, D.A.C. and V. Daggett, Methods for Molecular Dynamics Simulations of Protein Folding / Unfolding in Solution, Methods, 34, 112-120, 2004. [PDF]

Bennion, B.J. and V. Daggett, Counteraction of urea-induced protein denaturation by trimethylamine N-oxide: A chemical chaperone at atomic resolution, Proceedings of the National Academy of Sciences USA, 101, 6433-6438, 2004. [PDF]

Sato, S., Religa, T., Daggett, V. and A.R. Fersht, Testing protein-folding simulations by experiment: B domain of protein A, Proceedings of the National Academy of Sciences USA, 101, 6952-6956, 2004. [PDF]

Jemth, P., Gianni, S., Day, R., Li, B., Johnson, C.M., Daggett, V. and A.R. Fersht, Demonstration of a low energy on-pathway intermediate in a fast-folding protein by kinetics, protein engineering, and simulation, Proceedings of the National Academy of Sciences USA, 101, 6450-6455, 2004. [PDF]

DeMarco, M.L. and V. Daggett, From Conversion to Aggregation: Protofibril Formation of the Prion Protein, Proceedings of the National Academy of Sciences USA, 101, 2293-2298, 2004. [PDF]

Mayor, M., Guydosh, N.R., Johnson, C.M., Grossmann, J.G., Sato, S., Jas, G.S., Freund, S.M.V., Alonso, D.O.V., Daggett, V. and A.R. Fersht. The complete folding pathway of a protein from nanoseconds to microseconds, Nature, 421, 863-867, 2003. [PDF]