PORTING THE DEZYMER PROTEIN DESIGN PROGRAM TO A MULTI-USER SUPERCOMPUTING ENVIR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 使蛋白质受体和酶设计程序DEZYMER用于 多用户超级计算环境是这项提议的重点。 计算蛋白质方法产生设计蛋白质的最新进展 具有所需的结构和功能。成功创建受体结合 蛋白质包括使用Hellinga实验室的计算方法 在硫氧还蛋白[1，2]中创建金属离子结合部位的DEZYMER程序 和一组细菌中一系列无关配体的受体 周质结合蛋白(PBP)[3-6]。此外，使用DEZYMER， 磷酸丙糖异构酶(TIM)的酶活性是最近设计的 在缺乏先前催化特性的蛋白质支架中。这些 成果表明，生物物理理论和计算水平 现在可以获得电力，以便进入这些曾经难以解决的领域 有问题。我们对扩展该计划的能力感兴趣 以及用户对程序的可访问性。考虑到这一点，我们建议 在国家超级计算环境中测试和适应DEZYMER代码。 DEZYMER程序是一个内存密集型程序，它在 并行计算环境。该计划目前仅可用 在Hellinga实验室内(Homme Hellinga教授，杜克大学医学院 中心)，我们有一个60节点(120 Athlon处理器)的集群在运行 带有PVM的Linux。DEZYMER由C源代码组成，到目前为止 已成功部分移植到Apple Mac(PowerPC G4处理器) 电脑。为了最终使DEZYMER计划 可获得并拓宽这种受体和酶的设计方法，我们的目标是 在超级计算环境中测试和调整DEZYMER代码 思想。最初我们想把代码转移到匹兹堡 超级计算中心将超级计算机用于非常小规模的测试 通过发展分配委员会(发援会)的赠款。 在理论和方法上仍有很大的进步。 在理性计算蛋白质受体和酶的重新设计中制造[8，9]。 一个广泛适用于酶设计的程序将提供许多 为其他研究人员提供参与设计研究的机会。 在计算方面，将DEZYMER带入国家超级计算环境 将允许资源较少的年轻研究人员也参与 使用DEZYMER程序进行研究。从科学上讲， DEZYMER计算方法应该允许它适用于任何 具有已知高分辨率晶体结构的支架蛋白和大分子 足够的装订袋来容纳基材/产品。 参考文献 1.Benson，D.E.，M.S.Wisz和H.W.Hellinga，Rational Design of 新生金属酶。《南洋理工大学学报》，S A，2000。97(12)：第6292-7页。 2.Benson，D.E.等人，通过以下方法构建一种新的氧化还原蛋白 合理设计：将二硫键转化为单核 铁硫中心。生物化学，1998。37(20)：第7070-6页。 3.Dwyer，M.A.，L.L.Looger和H.W.Hellinga，计算设计 一种控制细菌基因表达的锌受体。Proc Natl Acad S，2003。第100(20)页：11255-60页。 4.De Lorimier，R.M.等，荧光生物传感器的构建 一家人。《蛋白质科学》，2002。11(11)：第2655-75页。 5.Benson，D.E.，A.E.Haddy和H.W.Hellinga，转化麦芽糖 通过计算设计将受体转化为新生的双核铜加氧酶。 生物化学，2002。41(9)：第362-9页。 6.Looger，L.L.等，受体和传感器的计算设计 具有新功能的蛋白质。《自然》，2003年。423(6936)：第185-90页。 7.Dwyer，M.A.，L.L.Looger和H.W.Hellinga，计算设计 一种生物活性的酶。《科学》，2004年。304(5679)：1967-71页。 8.Kraut，D.A.，K.S.Carroll和D.Herschlag，酵素挑战 机械学和能量学。Annu Rev Biochem，2003。72：第517-71页。 9.Bolon，D.N.，C.A.Voigt和S.L.Mayo，de nevo Design of 生物催化剂。Curr Opin Chem Biol，2002。6(2)：第125-9页。

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.