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

将 DEZYMER 蛋白质设计程序移植到多用户超级计算环境

基本信息

批准号：
7601391
负责人：
KATARINA S MIDELFORT
金额：
$ 0.03万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7601391
关键词：
Academic Medical Centers Achievement Apple Binding Binding Proteins Binding Sites Biochemistry Biosensor Code Computer Retrieval of Information on Scientific Projects Database Computers Copper Development Disulfides Environment Enzymes Facility Construction Funding Category Family Funding Gene Expression Grant Institution Iron Ligands Linux Maltose Memory Metal Ion Binding Methods Mind Mononuclear Murine pneumonia virus Nature Oxidation-Reduction Oxygenases Periplasmic Binding Proteins Proteins Range Research Research Design Research Personnel Resolution Resources Running Scaffolding Protein Science Source Source Code Structure Sulfur Supercomputing Testing Thioredoxin Triose-Phosphate Isomerase United States National Institutes of Health design desire enzyme mechanism interest metalloenzyme novel parallel computing programs receptor receptor binding sensor success supercomputer theories

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是中心，不一定是研究者的机构。采用蛋白质受体和酶设计程序 DEZYMER，多用户超级计算环境是该提案的重点。计算蛋白质方法的最新进展产生了设计蛋白质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 实验室的计算方法用于在硫氧还蛋白中创建金属离子结合位点的 DEZYMER 程序[1, 2] 以及一组细菌中一系列不相关配体的受体周质结合蛋白（PBP）[3-6]。此外，使用 DEZYMER，最近设计了磷酸丙糖异构酶（TIM）酶活性在缺乏先前催化特性的蛋白质支架中[7]。这些成果表明生物物理理论和计算水平现在可以利用力量来解决这些曾经棘手的问题问题。我们有兴趣扩展该计划的功能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调整 DEZYMER 代码。 DEZYMER 程序是一个内存密集型程序，运行在并行计算环境。该程序目前仅可用 Hellinga 实验室内（杜克大学医学院 Homme Hellinga 教授中心），我们正在运行一个 60 个节点（120 个 Athlon 处理器）的集群带 PVM 的 Linux。 DEZYMER 由 C 源代码组成，迄今为止已成功部分移植到 Apple Mac（PowerPC G4 处理器）电脑。努力最终使 DEZYMER 计划更加出色易于使用并拓宽这种受体和酶设计方法，我们的目标是在超级计算环境中测试和调整 DEZYMER 代码头脑。最初我们想将代码移植到匹兹堡超级计算中心用于小规模测试的超级计算机通过发展分配委员会 (DAC) 拨款。理论和方法上仍需取得巨大进展合理计算蛋白质受体和酶重新设计[8, 9]。一个广泛适用的酶设计工作程序将提供许多其他研究人员参与设计研究的机会。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。从科学角度来说， DEZYMER 计算方法应使其适用于任何支架蛋白具有已知的高分辨率晶体结构和大的足够的结合袋来容纳基材/产品。参考 1. Benson，D.E.，硕士维兹，H.W. Hellinga，理性设计新生金属酶。美国国家科学院院报，2000 年。97(12)：第 14 页。 6292-7。 2. Benson, D.E. 等人，通过构建新型氧化还原蛋白合理设计：将二硫桥转变为单核桥铁硫中心。生物化学，1998。37(20)：p。 7070-6。 3. Dwyer, M.A.、L.L. Looger 和 H.W.海林加，计算设计控制细菌基因表达的 Zn2+ 受体。国家科学院院刊美国科学，2003 年。100(20)：p。 11255-60。 4. de Lorimier, R.M. 等人，荧光生物传感器的构建家庭。蛋白质科学，2002。11(11)：p。 2655-75。 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）：p。 3262-9。 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。423（6936）：第。 185-90。 7. Dwyer，M.A.，L.L. Looger，和 H.W.海林加，计算设计一种具有生物活性的酶。科学，2004。304（5679）：第。 1967-71。 8.克劳特，D.A.，K.S. Carroll 和 D. Herschlag，酶的挑战机制和能量学。生物化学年鉴，2003 年。72：p。 517-71。 9. 博隆，DN，C.A.沃伊特，S.L.梅奥从头设计生物催化剂。当前化学生物学观点，2002。6(2)：p。 125-9。