Understanding Enzymatic Hydrolysis Mechanisms using Computer Simulations

三磷酸鸟苷（GTP）和其他核苷酸通过特定的酶水解在许多生命过程中起着重要作用。尽管对一系列不同的这种切割蛋白进行了大量的实验和理论研究，但核苷酸水解的机制仍然很大程度上是未知的。这里研究的蛋白质是GTPase“人鸟苷酸结合蛋白1”（hGBP1）。之所以选择它，是因为它具有特别丰富的反应序列，其活性中心首先将GTP水解为GDP，最后连续两步水解为GMP。这种性质使GTPase成为使用第一性原理方法研究这种催化过程的一个很好的体系。因此，该项目的总体目标是详细阐明hGBP1中GTP和GDP水解步骤的反应机制，利用最先进的多尺度模拟技术，使我们能够在蛋白质的环境条件下阐明完全原子水平上的机制。

The hydrolysis of guanosine triphoshate (GTP) and other nucleotides through specific enzymes plays an important role in many life-giving processes. Despite intense experimental and theoretical research on a range of different such cleaving proteins the mechanism of nucleotide hydrolysis still remains largely unknown. The protein under investigation here is the GTPase “human guanylate binding protein 1” (hGBP1). It was chosen as it exhibits a particularly rich reaction sequence by which its active center hydrolyses GTP first to GDP and finally to GMP in two consecutive steps. This property, amongst others, makes this GTPase an excellent system on which to study such catalytical processes using first principles methods. Therefore the general aim of this project is the detailed elucidation of the reaction mechanisms of both the GTP and GDP hydrolysis steps in hGBP1 making use of state of the art multiscale simulation techniques which allow us to elucidate the mechanisms on the fully atomistic level at ambient conditions in the protein.