Design of New Enzyme Catalysts

新型酶催化剂的设计

• 批准号: 8228008
• 负责人: KENDALL N HOUK
• 金额: $ 30.02万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228008
• 关键词: 3-Dimensional; Amino Acid Sequence; Amino Acids; Benchmarking; Binding; Binding Sites; Biological; Biological Models; Catalytic Domain; Collaborations; Data; Development; Enzymes; Exhibits; Goals; Grant; Herbicides; Lead; Measures; Mechanics; Methods; Molecular; Molecular Conformation; Mutation; Nature; Peptide Sequence Determination; Pesticides; Pharmacologic Substance; Protein Databases; Proteins; Reaction; Research; Side; Structure; Techniques; Technology; Testing; Uncertainty; Universities; Washington; base; catalyst; combinatorial; computational chemistry; computerized tools; design; enzyme mechanism; mutant; novel; public health relevance; quantum; reaction rate; tool

DESCRIPTION (provided by applicant): The goals of this research are to develop computational tools to design enzyme catalysts for reactions not found in nature. Catalytic binding sites for several types of reactions will be designed, based upon both covalent and noncovalent catalytic mechanisms. Combinatorial exploration of potential side-chain catalytic groups, followed by quantum mechanical testing of optimum catalytic arrangements will lead to a hierarchy of potential catalytic sites. Our collaborators, David Baker and his group, will use the coordinates of the designed catalytic sites to predict sequences that will fold into a catalytic site with this geometry. QM and QM/MM methods will be tested and developed in our lab to predict which of the designed proteins are likely to be the best catalysts. The proteins will be synthesized by the Baker group with standard molecular biological techniques, and in collaboration we will test the catalytic activity and mechanisms of these new proteins. Emphasis is on the development of efficient methods for the prediction of effective protein catalysts, and these methods will be tested against known data on enzymes and mutants that have different catalytic proficiencies. PUBLIC HEALTH RELEVANCE: During this grant period, we will develop and use the tools of computational chemistry to design novel enzymes. Our emphasis will be to demonstrate that we can do what has never been done before: design a functioning enzyme from scratch, starting with ideas about a catalytic site and ending with a fully functioning enzyme for a non-natural reaction. The initial target reactions will be of use in the synthesis of pharmaceutical targets and for the decomposition of a broad class of compounds utilized as pesticides and herbicides.

描述（由申请人提供）：本研究的目标是开发计算工具来设计自然界中未发现的反应的酶催化剂。将根据共价和非共价催化机制设计几种类型反应的催化结合位点。对潜在侧链催化基团的组合探索，然后对最佳催化排列进行量子力学测试，将产生潜在催化位点的层次结构。我们的合作者 David Baker 和他的团队将使用设计的催化位点的坐标来预测将折叠成具有这种几何形状的催化位点的序列。我们的实验室将测试和开发 QM 和 QM/MM 方法，以预测哪些设计的蛋白质可能是最好的催化剂。这些蛋白质将由贝克小组利用标准分子生物学技术合成，我们将合作测试这些新蛋白质的催化活性和机制。重点是开发有效的方法来预测有效的蛋白质催化剂，并且这些方法将根据具有不同催化能力的酶和突变体的已知数据进行测试。 公共卫生相关性：在资助期内，我们将开发和使用计算化学工具来设计新型酶。我们的重点是证明我们可以做以前从未做过的事情：从头开始设计一种功能酶，从催化位点的想法开始，到非自然反应的功能齐全的酶结束。最初的目标反应将用于药物目标的合成以及用作杀虫剂和除草剂的多种化合物的分解。

项目成果

Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis.

• DOI: 10.1038/nature10865
• 发表时间: 2012-03-04
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Hotta, Kinya;Chen, Xi;Paton, Robert S.;Minami, Atsushi;Li, Hao;Swaminathan, Kunchithapadam;Mathews, Irimpan I.;Watanabe, Kenji;Oikawa, Hideaki;Houk, Kendall N.;Kim, Chu-Young
• 通讯作者: Kim, Chu-Young

Evolution of a Unified Strategy for Complex Sesterterpenoids: Progress toward Astellatol and the Total Synthesis of (-)-Nitidasin.

• DOI: 10.1002/chem.201501423
• 发表时间: 2015-09-21
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Hog DT;Huber FM;Jiménez-Osés G;Mayer P;Houk KN;Trauner D
• 通讯作者: Trauner D

The role of distant mutations and allosteric regulation on LovD active site dynamics.

• DOI: 10.1038/nchembio.1503
• 发表时间: 2014-06
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Jimenez-Oses, Gonzalo;Osuna, Silvia;Gao, Xue;Sawaya, Michael R.;Gilson, Lynne;Collier, Steven J.;Huisman, Gjalt W.;Yeates, Todd O.;Tang, Yi;Houk, K. N.
• 通讯作者: Houk, K. N.

Conformational analysis of a nitroxide side chain in an α-helix with density functional theory.

用密度泛函理论对 α 螺旋中氮氧侧链进行构象分析。

• DOI: 10.1021/jp108871m
• 发表时间: 2011
• 期刊: The journal of physical chemistry. B
• 作者: Warshaviak,DoraToledo;Serbulea,Laura;Houk,KN;Hubbell,WayneL
• 通讯作者: Hubbell,WayneL

Computational design of enone-binding proteins with catalytic activity for the Morita-Baylis-Hillman reaction.

• DOI: 10.1021/cb3006227
• 发表时间: 2013-04-19
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Bjelic, Sinisa;Nivon, Lucas G.;Celebi-Oelcuem, Nihan;Kiss, Gert;Rosewall, Carolyn F.;Lovick, Helena M.;Ingalls, Erica L.;Gallaher, Jasmine Lynn;Seetharaman, Jayaraman;Lew, Scott;Montelione, Gaetano Thomas;Hunt, John Francis;Michael, Forrest Edwin;Houk, K. N.;Baker, David
• 通讯作者: Baker, David