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，目前还缺乏对这些动力学的精确的分子理解。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，以及设计具有比自然产生的蛋白质更好的催化性能的新蛋白质。这项研究的最终目标是理解生物系统中动力学和催化之间的相互作用，这一研究将得到该奖学金的支持。将进一步发展计算和理论方法来探索这种相互作用，并将该方法应用于具有生物学意义的系统，以获得其活动的详细分子图像。特别是，系统研究将是二氢叶酸还原酶(DHFR)和金属β-内酰胺酶。前者对于维持细胞内用于生物合成的四氢呋喃是很重要的。后一种酶与细菌耐药性有关。因此，对这些系统的催化循环的详细了解可能有助于药物设计。该申请者的角色将是进一步发展理论和计算方法。理论研究将与Wright和Dyson的核磁共振小组密切合作，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.