Head-Gordon, Teresa

Teresa Head-Gordon Department Bioengineering, UC Berkeley Major Research Interest: Computational Biology/Bioinformatics Phone: 510-486-7365 Email: This e-mail address is being protected from spam bots, you need JavaScript enabled to view it Date Available: Anytime after 10/1/00 Project Type Funding Rotation Yes NIH Yes Summer Yes Private Foundation   Thesis Yes Other Yes Project Titles: Minimalist Models for Annotating Whole Genomes Global Optimization Approaches to Protein Structure Prediction Theory/Experiment: Hydration Forces in Folding of Proteins Minimalist Models for Annotating Whole Genomes Abstract: While the experimental effort in structural genomics is focused on providing new fold classifications, computation and theory will play a complementary role of completing structural, kinetic, and thermodynamic information across whole genomes. We have now completed multiple studies at a simplified level of description of protein folding addressing issues of protein design, the folding of complex topologies and larger proteins, and the ability to reproduce thermodynamic and kinetic changes upon sequence mutation. In combination we believe they indicate the utility of this level of modeling as a productive step forward given current computational limits for feasibility of genomic-scale modeling. [1] J. M. Sorenson & T. Head-Gordon (1998). Fold & Design 3, 523-534. [2] J. M. Sorenson & T. Head-Gordon (1999). Proteins: Structure, Function, Genetics 37, 582-91. [3] J. M. Sorenson & T. Head-Gordon (2000). J. Comp. Bio., in press. [4] T. Head-Gordon and J. Wooley (2000). IBM Research Journal on Deep Computing in the Life Sciences, B. Robson, J. Coffin, W. Swope, editors, in press. [5] J. M. Sorenson & T. Head-Gordon (2000). Toward minimalist models of larger proteins: a ubiquitin-like protein. Submitted to Proteins: Structure, Function, Genetics Global Optimization Approaches to Protein Structure Prediction Abstract: The protein structure prediction problem is to determine the three-dimensional arrangement of the protein molecule, given a protein-solvent potential or free energy surface in accord with the amino acid sequence. This energy surface is difficult to model reliably in a global sense, i.e. to ensure that all misfolds are higher in energy than the correctly folded conformation, and the "rugged landscape" topography of this surface defines the underlying difficulty in finding the native structure minimum. We have developed a mathematical optimization approach that makes good predictions of certain aspects of protein structure such as a-helices, b-sheets, and coil regions by a neural network, and then manifest the prediction as restraints to use within both a local optimization algorithm and as guidance within various global optimization frameworks. The "implicit" hydration potentials between amino acids in solution derived from experiment/simulation have been used to define new energy functions for structure prediction. We would also like to initiate the combined use of our optimization approach with protein fold recognition algorithms to refine low-resolution fold predictions to higher level structural predictions as a means of structurally and functionally annotating whole genomes. These problems are computationally intensive, and require effective parallelization implementations to be tractable. S. Crivelli, T. Head-Gordon, R. H. Byrd, E. Eskow, R. Schnabel (1999). Lecture Notes in Computer Science, Euro-Par '99, P. Amestoy, P. Berger, M. Dayde, I. Duff, V. Fraysse, L. Giraud, D. ruiz (eds.), pg. 578-585. S. Crivelli, T. M. Philip, R. Byrd, E. Eskow, R. Schnabel, R. C. Yu, T. Head-Gordon (2000). Proceedings for New Trends in Computational Methods for Large Molecular Systems. Computers & Chemistry 24, 489-497. A. Azmi, R. H. Byrd, E. Eskow, R. Schnabel, S. Crivelli, T. M. Philip, T. Head-Gordon (2000). Optimization in Computational Chemistry and Molecular Biology: Local and Global Approaches, C. A. Floudas and P. M. Pardalos, editors (Kluwer Academic Publishers, Netherlands), 1-18. S. Crivelli & T. Head-Gordon (2000). A Hierarchical Approach for Parallelization of Large Tree Searches. Submitted to J. Parallel & Distributed Computing. Theory/Experiment: Hydration Forces in Folding of Proteins Combining solution scattering experiments and molecular dynamics simulations has allowed us to determine the solvation structure and potential of mean force of amino acid association in water as a function of solute concentration. The unification of the theoretical and experimental work is the development or discovery of effective amino acid interactions that implicitly includes the effects of aqueous solvent, that can be shown to deeply influence the kinetics, thermodynamics of protein folding, and to use as implicit solvation models in protein structure prediction. We are currently extending these experiments and simulations to temperature variations in order to characterize protein stability and flexibility for proteins found in thermophiles and hyperthermophile organisms. The experimentally determined solvation of amino acid monomers will be extended to real protein chains by considering the role of hydration in stabilizing molten globule intermediates of a-lactalbumin. A. Pertsemlidis, A. K. Soper, J. M. Sorenson & T. Head-Gordon (1999). Proc. Natl. Acad. Sci. 96, 481-486. J. M. Sorenson, G. Hura, A, K, Soper, A. Pertsemlidis & T. Head-Gordon (1999). Invited Feature Article for J. Phys. Chem. B, 103 5413-5426. G. Hura, J. M. Sorenson, R. M. Glaeser & T. Head-Gordon (1999). Perspectives in Drug Discovery and Design 17, 97-118. G. Hura, J. Sorenson, R.M. Glaeser & T. Head-Gordon (2000). A quality x-ray scattering experiment on liquid water at ambient conditions. J. Chem. Phys., in press J. Sorenson, G. Hura, R.M. Glaeser & T. Head-Gordon (2000). What can x-ray scattering tell us about the radial distribution functions of water? J. Chem. Phys., in press.