The principal objective of this proposal is to use T4 lysozyme as a model system to better understand the factors that determine the folding, stability, structure and function of proteins. The specific research to be accomplished includes the following: (1) The body of structural, thermodynamic, and kinetic information on mutant T4 lysozymes will be used, both within the group and in collaboration with others, to test and improve computer-assisted protein design. (2) An attempt will be made to simplify the protein folding problem by identifying which residues, or combination of residues, are critical for the folding and stability of T4 lysozyme. We want to understand, not only how given residues contribute to stability, but also the relative importance of local versus non-local effects in protein folding. (3) Cavities within T4 lysozyme will be exploited to better understand protein-ligand interaction and to optimize rational approaches to drug selection and docking (in collaboration with B. Shoichet). (4) We will attempt to engineer a long-distance, ligand-induced conformational switch in a protein. (5) Neutron crystallography will be used to characterize catalytic intermediates and to compare dynamical processes in crystals of T4 lysozyme with those in solution. (6) The contribution of solvent to protein folding and stability will be further analyzed. (7) The effects of pressure on proteins with cavities will be determined.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Flicker, Paula F
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University of Oregon
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Baase, Walter A; Liu, Lijun; Tronrud, Dale E et al. (2010) Lessons from the lysozyme of phage T4. Protein Sci 19:631-41
Liu, Lijun; Marwitz, Adam J V; Matthews, Brian W et al. (2009) Boron mimetics: 1,2-dihydro-1,2-azaborines bind inside a nonpolar cavity of T4 lysozyme. Angew Chem Int Ed Engl 48:6817-9
Mooers, Blaine H M; Tronrud, Dale E; Matthews, Brian W (2009) Evaluation at atomic resolution of the role of strain in destabilizing the temperature-sensitive T4 lysozyme mutant Arg 96 --> His. Protein Sci 18:863-70
Liu, Lijun; Baase, Walter A; Matthews, Brian W (2009) Halogenated benzenes bound within a non-polar cavity in T4 lysozyme provide examples of I...S and I...Se halogen-bonding. J Mol Biol 385:595-605
Liu, Lijun; Baase, Walter A; Michael, Miya M et al. (2009) Use of stabilizing mutations to engineer a charged group within a ligand-binding hydrophobic cavity in T4 lysozyme. Biochemistry 48:8842-51
Matthews, Brian W; Liu, Lijun (2009) A review about nothing: are apolar cavities in proteins really empty? Protein Sci 18:494-502
Mooers, Blaine H M; Baase, Walter A; Wray, Jonathan W et al. (2009) Contributions of all 20 amino acids at site 96 to the stability and structure of T4 lysozyme. Protein Sci 18:871-80
Liu, Lijun; Quillin, Michael L; Matthews, Brian W (2008) Use of experimental crystallographic phases to examine the hydration of polar and nonpolar cavities in T4 lysozyme. Proc Natl Acad Sci U S A 105:14406-11
Collins, Marcus D; Quillin, Michael L; Hummer, Gerhard et al. (2007) Structural rigidity of a large cavity-containing protein revealed by high-pressure crystallography. J Mol Biol 367:752-63
Yousef, Mohammad S; Bischoff, Nicole; Dyer, Collin M et al. (2006) Guanidinium derivatives bind preferentially and trigger long-distance conformational changes in an engineered T4 lysozyme. Protein Sci 15:853-61

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