COMPUTER SIMULATION OF CORRELATED DYNAMICS DURING LIGAND BINDING & CATALYSIS

该项目将使用先进的计算机模拟技术， 研究与DFHR中催化事件相关的动力学和波动 和β-内酰胺酶，与实验组密切合作， NMR和诱变数据。该分析将扩展传统的分子 以新的方式研究长期相关运动的动力学模拟 距离尺度和开发催化途径的详细模型， 使用以下技术。 (a)关键动力学中间态的分子动力学模拟 其特征在于实验的DHFR的催化循环，提供了一个 这些分子的涨落和动力学研究的基础 系统和这些之间的耦合催化功能。类似 将对进化上不太成熟的酶进行模拟 金属β-内酰胺酶系统。 (b)新化合物产生的DHFR中的催化途径模型 轨迹技术生成技术，找到过渡态 以及连接催化中间体（或 通过核磁共振、晶体学和突变分析产生它们的类似物。 (c)DHFR和β- 游离和配体结合形式的内酰胺酶，基于提出的结构 模型的催化中间状态和脱辅基酶，研究 长波长，低频相关运动，可以影响 这些制度的整体刚性。从这些衍生的运动模型 将创建研究，可调参数，以适应核磁共振弛豫 数据 (d)与项目3合作，完善解决方案结构， 游离的和与抑制剂复合的β-内酰胺酶。这一目标 将首先涉及量子力学基础模型的发展 对活性位点进行结构建模。

This project will use developed computer simulation techniques to study dynamics and fluctuations associated with catalytic events in DFHR and beta-lactamase, working closely with experimental groups to interpret NMR and mutagenesis data. The analysis will extend conventional molecular dynamics simulations in novel ways to study correlated motions at long distance scales and to develop detailed models of catalytic pathways, using the following techniques. (a) Molecular dynamics simulations on key kinetic intermediate states characterized experimentally for the catalytic cycle of DHFR, providing a basis for the study of fluctuations and dynamics of these molecular systems and the coupling between these to catalytic function. Similar simulations will be performed for the evolutionally less mature enzyme system of metallo beta-lactamase. (b) Models for catalytic pathways in DHFR generated by novel trajectory techniques generation techniques that find transition states and reaction paths to connect structures of catalytic intermediates (or their analogues generated by NMR, crystallography and mutational analysis. (c) Harmonic and quasiharmonic analyses of both DHFR and beta- lactamase in free and ligand-bound forms, based on proposed structural models of catalytic intermediate states and the apo-enzymes, to study long-wavelength, low-frequency correlated motions that can affect the overall rigidity of these system. Motional models derived from these studies will be created, with adjustable parameters to fit NMR relaxation data. (d) Collaboration with Project 3 to refine a solution structure of beta-lactamase both free and in complex with inhibitors. This objective will involve first the development of quantum mechanically based models for the bimetallic active site followed by structural modeling.