Computer Simulations of Enzymes

酶的计算机模拟

基本信息

批准号：
8204445
负责人：
Weitao Yang
金额：
$ 30.43万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204445
关键词：
Active Sites Address Affect Amino Acids Activation Bacteria Bacterial Pili Biochemical Process Biological Biological Process Cell Wall Chemicals Cleaved cell Complex Computer Simulation Dependence Development Electronics Environment Enzyme Inhibitor Drugs Enzymes Free Energy Freedom Funding Goals Individual Investigation Ions Lead Life Link Mechanics Methodology Methods Modeling Molecular Organism Peptides Peptidyltransferase Pharmaceutical Preparations Phase Pilum Play Process Progress Reports Protein Conformation Proteins Reaction Research Rest Roentgen Rays Role Sampling Scheme Side Simulate Solutions Solvents Structure Surface System Tryptophan Tryptophan-tRNA Ligase Work base biological systems chemical reaction cofactor cost density design inhibitor/antagonist insight molecular dynamics pathogenic bacteria practical application protonation public health relevance quantum research study simulation sortase theories tool

项目摘要

DESCRIPTION (provided by applicant): Based on structural information from X-ray and NMR experiments, computational simulations performed using molecular dynamics and the quantum mechanical/molecular mechanical (QM/MM) approach are able to describe the mechanisms of chemical reactions catalyzed by enzymes. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum mechanical approaches, however at a much higher computational cost compared with corresponding semiempirical quantum mechanical approaches. Thus reaction path and activation free energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation timescales and phase space sampling. This proposal aims to develop further the ab initio QM/MM methodology and its application to the investigation of the mechanisms of chemical reactions in important enzymes. The long-term goal is to develop and establish density functional theory-based QM/MM simulation as an equal partner with experiments for the study of the structure and chemical reactions of enzymes and to provide detailed insight into chemical reaction mechanisms in biological systems. The ab initio QM/MM-MFEP method has been developed recently to overcome some of the difficulties encountered in previous ab initio QM/MM approaches for obtaining minimum energy reaction paths. Previous total energy-based methods suffer from a dependence on the local conformations of the protein/solvent environment. In the QM/MM-MFEP method, the reaction system is described via the potential of mean force (PMF) surface of the QM subsystem in the active site, while the large number of MM degrees of freedom describing the rest of the protein and solvent are statistically averaged. This proposal aims to develop the QM/MM-MFEP method further into a comprehensive and accurate method for the simulation of reaction processes in solution and in enzymes using ab initio QM/MM methods. The QM/MM methodology will be used to investigate the reaction mechanism of several important enzymes: (1) Tryptophanyl-tRNA synthetase, which catalyzes the amino acid activation process; (2) Sortase, which recognizes and cleaves peptides, and then covalently links the peptides to cell walls, in association with Gram-positive pathogenic bacteria; and (3) Gram-positive bacterial pili, which play important roles in the biological functions of many bacteria. The proposed work will lead to the advancement of theoretical methodology and the understanding of important enzyme reaction mechanisms. In addition, it will also serve to aid in the design of new drugs and enzyme inhibitors. PUBLIC HEALTH RELEVANCE: This proposal aims at developing methods for simulating chemical processes catalyzed by enzymes, and investigating the catalytic mechanisms of certain important enzymes. The proposed work will lead to significant advances in research tools for studying enzymes. Because enzymes catalyze most of the chemical processes in living organisms, it will contribute to the understanding of life processes, as well as aiding in the design of inhibitors and drugs.

描述（由申请人提供）：基于X射线和NMR实验的结构信息，使用分子动力学和量子力学/分子力学（QM/MM）方法进行的计算模拟能够描述酶催化的化学反应的机制。从头算 QM/MM 方法利用了相关量子力学方法的准确性和可靠性，但与相应的半经验量子力学方法相比，计算成本要高得多。因此，基于从头开始的 QM/MM 方法的反应路径和活化自由能计算在模拟时间尺度和相空间采样方面遇到了独特的挑战。该提案旨在进一步发展从头开始的 QM/MM 方法及其在重要酶化学反应机制研究中的应用。长期目标是开发和建立基于密度泛函理论的 QM/MM 模拟，作为酶结构和化学反应研究实验的平等伙伴，并为生物系统中的化学反应机制提供详细的见解。最近开发了从头计算 QM/MM-MFEP 方法，以克服以前从头计算 QM/MM 方法获得最小能量反应路径时遇到的一些困难。以前基于总能量的方法依赖于蛋白质/溶剂环境的局部构象。在 QM/MM-MFEP 方法中，反应系统通过活性位点 QM 子系统的平均力 (PMF) 表面势来描述，而大量 MM 自由度描述了蛋白质和溶剂的其余部分进行统计平均。该提案旨在将 QM/MM-MFEP 方法进一步发展为一种全面、准确的方法，用于使用从头开始的 QM/MM 方法模拟溶液和酶中的反应过程。 QM/MM方法将用于研究几种重要酶的反应机制：（1）色氨酰-tRNA合成酶，催化氨基酸活化过程；（2）分选酶，识别并裂解肽，然后将肽共价连接到细胞壁上，与革兰氏阳性病原菌结合； (3)革兰氏阳性细菌菌毛，在许多细菌的生物学功能中发挥重要作用。所提出的工作将导致理论方法的进步和对重要酶反应机制的理解。此外，它还将有助于新药和酶抑制剂的设计。公共健康相关性：该提案旨在开发模拟酶催化化学过程的方法，并研究某些重要酶的催化机制。拟议的工作将导致酶研究工具的重大进步。由于酶催化生物体中的大部分化学过程，因此它将有助于理解生命过程，并有助于抑制剂和药物的设计。