Exploring Catalytic Modules in Alkaline Phosphatase by Computer Simulation

 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理解将有助于设计新的催化剂以及抑制酶的药物。该提案旨在了解碱性磷酸酶（AP）催化的一个潜在重要的新方面。AP催化磷酸盐转移，这是生物学和医学中最重要的反应之一，最近的实验提出该酶在活性位点使用“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。拟议中的计算机模拟将确定这种协同性如何在原子水平上起作用，以及它是否对其他酶很重要。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，用于酶的计算机模拟。目前可用的方法在涉及高电荷底物的反应中不稳定，并且对处理此类反应提出的改进将在酶学中具有有用的应用。

 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.