Exploring Catalytic Modules in Alkaline Phosphatase by Computer Simulation

通过计算机模拟探索碱性磷酸酶的催化模块

基本信息

批准号：
9057869
负责人：
DANIEL ROSTON
金额：
$ 5.61万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057869
关键词：
Active Sites Address Affect Alkaline Phosphatase Amino Acids Biochemical Reaction Biological Biology Biomimetics Catalysis Charge Communication Communities Computer Simulation Computing Methodologies Data Development Disease Drug Design Electrostatics Environment Enzymatic Biochemistry Enzymes Exhibits Felis catus Free Energy Generations Hybrids Hydrogen Bonding Indium Learning Measurement Medicine Metalloproteins Methods Modeling Mutation Pattern Pharmaceutical Preparations Phase Process Property Quantum Mechanics Reaction Research Research Personnel Role Scientist Source Speed Structure Students System Techniques Testing Therapeutic Training Transition Elements Work career catalyst density design enzyme mechanism enzyme model improved infancy inhibitor/antagonist inorganic phosphate insight metalloenzyme molecular mechanics mutant novel operation public health relevance research study simulation success theories

项目摘要

DESCRIPTION (provided by applicant): The proposed research will use state-of-the-art computer simulations to examine fundamental processes of enzyme catalysis. A deep understanding of the physical mechanisms of enzyme catalysis will illuminate both the design of new catalysts, as well as drugs that inhibit enzymes. The proposal aims to understand a potentially important, novel aspect of catalysis by the enzyme alkaline phosphatase (AP). AP catalyzes phosphate transfer, which is one of the most important reactions in biology and medicine, and recent experiments proposed that the enzyme uses "functional modules" at the active site to catalyze the reaction. The functional modules, consisting of a few amino acids each, display a previously unobserved mode of cooperativity. The proposed computer simulations will determine how this cooperativity works at an atomic level and whether it could be important for other enzymes. Additionally, in order to accurately model this enzyme, the proposed research will develop an improved method for computer simulations of enzymes. Currently available methods falter in reactions involving highly charged substrates, and the proposed improvements to treating such reactions will have useful applications in enzymology.

描述（由申请人提供）：拟议的研究将使用最先进的计算机模拟来检查酶催化的基本过程，对酶催化的物理机制的深入了解也将阐明新催化剂的设计。作为抑制酶的药物，该提案旨在了解碱性磷酸酶 (AP) 催化磷酸盐转移的潜在重要、新颖的方面，这是最重要的反应之一。在生物学和医学领域，最近的实验提出，酶在活性位点使用“功能模块”来催化反应，每个功能模块由几个氨基酸组成，显示出以前未观察到的协同模式。将确定这种协同性如何在原子水平上发挥作用，以及它对其他酶是否重要。此外，为了准确地模拟这种酶，拟议的研究将开发一种改进的方法，用于当前可用的反应方法。涉及高度收费底物，以及所提出的处理此类反应的改进将在酶学中具有有用的应用。