Biomolecular Interactions and Enzymatic Processes

生物分子相互作用和酶促过程

基本信息

批准号：
8922816
负责人：
JIALI GAO
金额：
$ 29.89万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-30 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8922816
关键词：
Address Amino Acids Area Binding Biochemical Process Biochemical Reaction Biological Biological Process Catalysis Cells Charge Chemicals Chemistry Coenzymes Comparative Study Complex Computer Simulation Computing Methodologies Coupled Data Development Disease Electron Transport Electronics Electrons Engineering Enzymes Evaluation Excision Flavin-Adenine Dinucleotide Free Energy Free Radicals Goals Grant Growth Heme Histones Hydrogen Iron Kinetics Knowledge Life Lysine Malignant Neoplasms Masks Mechanics Metabolism Methodology Methods Microscopic Modeling Molecular Nuclear Oxygen Pharmaceutical Preparations Pharmacologic Substance Photosynthesis Play Principal Investigator Procedures Process Property Protein Dynamics Protein Engineering Proteins Protons Reaction Research Research Project Grants Resolution Respiration Ribonucleotide Reductase Role Solutions Structure Techniques Testing Theoretical model Translations Veins Water aqueous arginyllysine biological systems cell growth chemical reaction cofactor computer studies demethylation density design enzyme mechanism epigenetic regulation histone modification improved inhibitor/antagonist insight interest methyl group molecular dynamics molecular orbital oxidation programs quantum research study simulation structural biology theories tool

项目摘要

DESCRIPTION (provided by applicant): A multi-faceted research project is directed aimed at computational studies of enzymatic processes in aqueous solution. The theoretical approach centers on molecular dynamics free energy simulations of enzymes, making use of combined quantum mechanical and molecular mechanical (QM/MM) methods. A major goal is to increase the capability of QM/MM methods and to achieve greater accuracy than conventional approaches. We propose to further improve the mixed molecular orbital and valence bond (MOVB) theory, coupled with the self-consistent charge tight-bonding density functional theory (SCC-DFTB) and extension to the CHARMM program with ab initio and DFT methods, such that the theoretical model can be conveniently calibrated, tested and used by experimental biochemists as a research tool to help interpret experiment findings. The MOVB method has been developed at theoretical levels that include ab initio and semiempirical molecular orbital and density functional theory. One goal of the present study is to incorporate the procedure into molecular dynamics simulation programs for effectively modeling enzymatic reactions. A major thrust of this project is to provide a deeper understanding of the underlying principles and mechanisms of enzymatic reactions. During this grant period, we focus on the catalytic mechanism of histone lysine demethylases with emphasis on the Jumonji C domain containing enzymes, which belong to a large class of enzymes that utilize a non-heme high- valent iron-oxo intermediate. Histone lysine demethylases along with other histone protein modifying enzymes play a critical role in epigenetic regulation and have been found to be associated with cancer development and progress. In addition, we seek to address the general properties of enzymatic proton-coupled electron transfer reactions and the effects of protein dynamics and enzyme reorganization energies on these processes. The MOVB method provides an important research tool to study these questions, and the results will be of general importance to protein engineering and inhibitor design. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：一个多面研究项目针对水溶液中酶促过程的计算研究。理论方法以酶的分子动力学自由能模拟为中心，利用了量子力学和分子机械（QM/mm）方法。一个主要目标是提高QM/mm方法的能力并获得比常规方法更高的准确性。我们建议进一步改善混合分子轨道和价键（MOVB）理论，再加上自动键合密度密度理论（SCC-DFTB），并使用Ab ab tif和DFT方法扩展到CHARMM程序，从而可以方便地校准，通过实验性的BioCriencational Interifore flastimential Biocrient flastimential Biocients工具，以实验性地进行了研究。 MOVB方法是在理论级别开发的，其中包括从头算和半经验分子轨道和密度功能理论。本研究的目标之一是将程序纳入分子动力学模拟程序中，以有效地建模酶促反应。该项目的主要目的是提供对酶促反应的基本原理和机制的更深入的理解。在这一赠款期间，我们关注组蛋白赖氨酸脱甲基酶的催化机制，重点是含有酶的Jumonji C结构域，这些酶属于利用非最高的高级铁 - 氧中间体的大型酶。组蛋白赖氨酸脱甲基酶以及其他组蛋白蛋白修饰酶在表观遗传调节中起关键作用，并被发现与癌症的发展和进步有关。此外，我们试图解决酶促质子偶联电子转移反应的一般特性，以及蛋白质动力学和酶重组能对这些过程的影响。 MOVB方法提供了研究这些问题的重要研究工具，结果对于蛋白质工程和抑制剂设计至关重要。 PHS 398/2590（修订版06/09）页面延续格式页面