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进行水解，在许多赋予生命的过程中发挥着重要的作用。尽管对一系列不同的这样的裂解蛋白进行了密集的实验和理论研究，但核苷酸水解的机制在很大程度上仍然不清楚。这里研究的蛋白质是GTP酶“人鸟苷结合蛋白1”(HGBP1)。选择它是因为它显示了一个特别丰富的反应序列，通过它的活性中心首先将GTP水解成GDP，最后经过两个连续的步骤生成GMP。这一性质使该GTP酶成为使用第一性原理方法研究此类催化过程的极佳系统。因此，本项目的总体目标是利用最先进的多尺度模拟技术详细阐明hGBP1中GTP和GDP水解步骤的反应机理，使我们能够在环境条件下阐明蛋白质中全原子水平的机理。

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.