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

• 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
• 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

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 适应蛋白质受体和酶设计程序Dezymer，以适应 多用户超级计算环境是该提案的重点。 计算蛋白方法的最新进展产生了设计的蛋白质 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 Labs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] 和一组细菌中一系列无关的配体的受体 周质结合蛋白（PBP）[3-6]。另外，使用dezymer， 最近设计了三糖磷酸异构酶（TIM）酶活性 在缺乏以前的催化特征的蛋白质支架中[7]。这些 成就表明生物物理理论和计算水平 现在可以访问电源以使这些曾经棘手 问题。我们有兴趣扩大程序的功能 以及对程序的用户可访问性。考虑到这一点，我们建议 在国家超级计算环境中测试并调整Dezymer代码。 Dezymer程序是一个内存密集的程序，在 并行计算环境。该程序目前仅可用 在Hellinga实验室（Homme Hellinga教授，杜克大学医学 中心）我们有一个60个节点（120 Athlon处理器）群集运行 带有PVM的Linux。 Dezymer由C源代码组成，到目前为止 成功地部分移植到Apple Mac（PowerPC G4处理器） 电脑。为了最终使Dezymer计划更多 我们的目标是可访问和扩展这种受体和酶设计方法 测试和调整Dezymer代码在超级计算环境中 头脑。最初，我们想将代码移到匹兹堡 超级计算中心超级计算机以非常小的规模进行测试 通过发展分配委员会（DAC）赠款。 仍然有很大的理论和方法论进步 在理性的计算蛋白受体和酶重新设计中制成[8，9]。 广泛适用的酶设计工作计划将为许多 其他研究人员参加设计研究的机会。 在计算上，将dezymer带入国家超级计算环境 将允许年轻资源更少的研究人员也参与 使用Dezymer计划进行研究。从科学上讲， Dezymer计算方法应允许其适用于任何 具有已知高分辨率晶体结构的脚手架蛋白质和较大的 足够的装订袋以包含底物/产品。 参考 1。Benson，D.E.，M.S。 Wisz和H.W. Hellinga，理性的设计 新生的金属酶。 Proc Natl Acad Sci u S A，2000。97（12）：p。 6292-7。 2。Benson，D.E。等，通过 理性设计：将二硫键转换为单核 铁硫心中心。生物化学，1998。37（20）：p。 7070-6。 3。Dwyer，M.A.，L.L。Looger和H.W. Hellinga，计算设计 控制细菌基因表达的Zn2+受体。 Proc Natl Acad Sci u s a，2003。100（20）：p。 11255-60。 4。DeLorimier，R.M。等人，荧光生物传感器的构造 家庭。蛋白质科学，2002。11（11）：p。 2655-75。 5。Benson，D.E.，A.E。Haddy和H.W. hellinga，转换麦芽糖 通过计算设计，受体进入新生的双核铜氧酶。 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。 Nature，2003。423（6936）：p。 185-90。 7。Dwyer，M.A.，L.L。Looger和H.W. Hellinga，计算设计 生物活性酶的。 Science，2004。304（5679）：p。 1967-71。 8。Kraut，D.A.，K.S。 Carroll和D. Herschlag，在酶中挑战 机制和能量学。 Annu Rev Biochem，2003。72：p。 517-71。 9。Bolon，D.N.，C.A。 Voigt和S.L. Mayo，从头设计 生物催化剂。 Curr Opin Chem Biol，2002。6（2）：p。 125-9。