COMPUTATIONAL STUDY OF DYNAMICS DURING ENZYME CATALYSIS

已知蛋白质动力学在酶催化过程中是必不可少的。然而，目前缺乏对这些动力学的精确分子理解。这样的图像将有助于理解为什么以及如何特定的蛋白质催化特定的反应。这将有助于设计抑制特定酶反应的新药，以及设计比天然蛋白质具有更好催化性能的新蛋白质。这项研究的最终目标是了解生物系统中动力学和催化作用之间的相互作用。计算和理论方法将进一步发展，以探讨这种相互作用和方法将应用于ti生物显着的系统，以获得详细的分子图片，他们的活动。特别是，将系统研究二氢叶酸还原酶（DHFR）和金属-b-内酰胺酶。前者在维持用于生物合成的THF的细胞内库中是重要的。后一种酶与细菌耐药性有关。因此，详细了解这些系统的催化循环可以帮助药物设计。该申请人的作用将是进一步发展理论和计算方法。理论研究将与Wright和Dyson的NMR小组密切合作，他们将对相同的系统进行实验研究。

DESCRIPTION Protein dynamics are known to be essential during enzyme catalysis. However, a precise molecular understanding of these dynamics is currently lacking. Such a picture would assist in understanding why and how particular proteins catalyze particular reactions. This would be useful in designing new drugs to inhibit specific enzymatic reactions as well as in designing new proteins to have better catalytic properties than naturally occurring proteins. The ultimate objective of this research, which this fellowship would support, is to understand the interaction between dynamics and catalysis in biological systems. Computational and theoretical methodology will be further developed to explore this interaction and the methodology will be applied ti biologically significant systems to obtain detailed molecular pictures of their activities. In particular, the systems studies will be dihydrofolate reductase (DHFR) and metallo-b-lactamase. The former is important in maintaining intracellular pools of THF which are used in biosynthesis. The later enzyme is implicated in bacterial drug resistance. So a detailed understanding of the catalytic cycles of these systems could assist in drug design. This applicant's role will be to further develop the theoretical and computational methodology. The theoretical investigations will be performed in close collaboration with the NMR groups of Wright and Dyson who will be conducting experimental studies of the same systems.