Computational biology; Prediction and design of protein interactions and interaction networks combining computational modeling and experimental analysis

We are interested in how biological molecules communicate with each other, and how this communication encodes the processing of information. How do biomolecules recognize one another, and how do their interactions transduce signals? How do molecules build up "modules" that act as "adaptors", "switches" and feedback-loops? How are modules wired together into the networks responsible for regulation and decision processes observed in biology?

To address these broad questions, we couple computational and experimental strategies. Our approaches range from the development of computational methods, high-resolution structural studies and thermodynamic analysis of molecular interactions to functional assays.

Computationally, we have developed a simple physical energy function for the prediction and design of protein-protein interactions, at the atomic level. Experimentally, we have applied this model to the computational redesign of a protein interface and have created an artificial DNA binding protein with new specificity. More recently, we have developed a computational strategy for the redesign of protein complexes to generate new pairs of interacting proteins.

We are now applying and extending our computational model at different "resolution", ranging from details of atom-atom interactions to cellular communication networks. We are aiming to develop more accurate methods to model the structural details of molecular interactions. Can new interactions and modules with defined properties be engineered? Ultimately we would like to apply computational and experimental methods to better understand how cellular processes are regulated by molecular communication.

Selected Publications:

Kortemme, T. and D. Baker (2004). "Computational design of protein-protein interactions." Curr Opin Chem Biol 8(1): 91-7. (Review)

Kortemme, T., L. A. Joachimiak, A. N. Bullock, A. D. Schuler, B. L. Stoddard and D. Baker (2004). "Computational redesign of protein-protein interaction specificity." Nat Struct Mol Biol 11(4): 371-9.

Morozov, A. V., T. Kortemme, K. Tsemekhman and D. Baker (2004). "Close agreement between the orientation dependence of hydrogen bonds observed in protein structures and quantum mechanical calculations." Proc Natl Acad Sci U S A 101(18): 6946-51.

Kortemme, T., A. V. Morozov and D. Baker (2003). "An orientation-dependent hydrogen bonding potential improves prediction of specificity and structure for proteins and protein-protein complexes." J Mol Biol 326(4): 1239-59.

Chevalier, B. S., T. Kortemme, M. S. Chadsey, D. Baker, R. J. Monnat and B. L. Stoddard (2002). "Design, activity, and structure of a highly specific artificial endonuclease." Mol Cell 10(4): 895-905.

Kortemme, T. and D. Baker (2002). "A simple physical model for binding energy hot spots in protein-protein complexes." Proc Natl Acad Sci U S A 99(22): 14116-21.