This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Adapting the protein receptor and enzyme design program, DEZYMER, for a multi-user supercomputing environment is the focus of this proposal. Recent advances in computational protein methods yielded designed proteins with desired structure and function. Success in creating receptor binding proteins include using the computational approach of the Hellinga labs DEZYMER program for creating metal ion binding sites in thioredoxin[1, 2] and receptors for a range of unrelated ligands in a group of bacterial periplasmic binding proteins (PBP)[3-6]. Additionally, using DEZYMER, triose phosphate isomerase (TIM) enzymatic activity was recently designed in a protein scaffold that lacked previous catalytic character[7]. These achievements indicate that the level of biophysical theory and computing power are now accessible to make inroads into these once intractable problems. We are interested in expanding the capabilities of the program and the user accessibility to the program. With this in mind, we propose to test and adapt the DEZYMER code in a national supercomputing environment. The DEZYMER program is a memory intensive program which runs in a parallel computing environment. The program is currently only available within the Hellinga lab (Prof. Homme Hellinga, Duke University Medical Center) where we have a 60 node (120 Athlon processor) cluster running Linux with PVM. DEZYMER consists of C source code and has so far been successfully partially ported to an Apple Mac (PowerPC G4 processor) computer. In an effort to ultimately make the DEZYMER program more accessible and broaden this receptor and enzyme design approach, we aim to test and adapt the DEZYMER code with the supercomputing environment in mind. Initially we would like to port the code over to the Pittsburgh Supercomputing Centers supercomputers for testing on a very small scale through a Development Allocations Committee (DAC) grant. There are still large theoretical and methodological advances to be made in rational computational protein receptor and enzyme redesign[8, 9]. A widely applicable program for enzyme design efforts will provide many opportunities for other researchers to participate in the design research. Computationally, bringing DEZYMER to a national supercomputing environment will allow younger researchers with less resources to also participate in research using the DEZYMER program. Scientifically, the generalizability of the DEZYMER computational approach should allow it to be applicable to any scaffold protein with a known high resolution crystal structure and a large enough binding pocket to contain the substrate/product. References 1. Benson, D.E., M.S. Wisz, and H.W. Hellinga, Rational design of nascent metalloenzymes. Proc Natl Acad Sci U S A, 2000. 97(12): p. 6292-7. 2. Benson, D.E., et al., Construction of a novel redox protein by rational design: conversion of a disulfide bridge into a mononuclear iron-sulfur center. Biochemistry, 1998. 37(20): p. 7070-6. 3. Dwyer, M.A., L.L. Looger, and H.W. Hellinga, Computational design of a Zn2+ receptor that controls bacterial gene expression. Proc Natl Acad Sci U S A, 2003. 100(20): p. 11255-60. 4. de Lorimier, R.M., et al., Construction of a fluorescent biosensor family. Protein Sci, 2002. 11(11): p. 2655-75. 5. Benson, D.E., A.E. Haddy, and H.W. Hellinga, Converting a maltose receptor into a nascent binuclear copper oxygenase by computational design. Biochemistry, 2002. 41(9): p. 3262-9. 6. Looger, L.L., et al., Computational design of receptor and sensor proteins with novel functions. Nature, 2003. 423(6936): p. 185-90. 7. Dwyer, M.A., L.L. Looger, and H.W. Hellinga, Computational design of a biologically active enzyme. Science, 2004. 304(5679): p. 1967-71. 8. Kraut, D.A., K.S. Carroll, and D. Herschlag, Challenges in enzyme mechanism and energetics. Annu Rev Biochem, 2003. 72: p. 517-71. 9. Bolon, D.N., C.A. Voigt, and S.L. Mayo, De novo design of biocatalysts. Curr Opin Chem Biol, 2002. 6(2): p. 125-9.
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