Design of New Enzyme Catalysts

新型酶催化剂的设计

• 批准号: 7782699
• 负责人: KENDALL N HOUK
• 金额: $ 30.37万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7782699
• 关键词: 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; Techniques; Technology; Testing; Uncertainty; Universities; Washington; base; catalyst; combinatorial; computational chemistry; computerized tools; design; enzyme mechanism; mutant; novel; public health relevance; quantum; reaction rate; three dimensional structure; 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。几种类型的反应的催化结合位点将被设计，基于共价和非共价催化机制。潜在的侧链催化基团的组合探索，其次是量子力学测试的最佳催化安排将导致潜在的催化位点的层次结构。我们的合作者，大卫贝克和他的小组，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。QM和QM/MM方法将在我们的实验室进行测试和开发，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Baker小组用标准的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。重点是有效的蛋白质催化剂的预测的有效方法的发展，这些方法将被测试对已知的数据酶和突变体，具有不同的催化profabrics。 公共卫生相关性：在此资助期间，我们将开发和使用计算化学的工具来设计新的酶。我们的重点将是证明我们可以做以前从未做过的事情：从头开始设计一个功能酶，从催化位点的想法开始，以一个功能齐全的酶为非自然反应结束。最初的靶向反应将用于合成药物靶点，并用于分解用作杀虫剂和除草剂的广泛类别的化合物。