Wu Ruibo, Hu Po, Wang Shenglong, Cao Zexing, Zhang Yingkai
Department of Chemistry, New York University, 100 Washington Square East, New York, NY 10003 USA.
J Chem Theory Comput. 2009 Dec 2;6(1):337. doi: 10.1021/ct9005322.
The different coordination modes and fast ligand exchange of zinc coordination has been suggested to be one key catalytic feature of the zinc ion which makes it an invaluable metal in biological catalysis. However, partly due to the well known difficulties for zinc to be characterized by spectroscopy methods, evidence for dynamic nature of the catalytic zinc coordination has so far mainly been indirect. In this work, Born-Oppenheimer ab initio QM/MM molecular dynamics simulation has been employed, which allows for a first-principle description of the dynamics of the metal active site while properly including effects of the heterogeneous and fluctuating protein environment. Our simulations have provided direct evidence regarding inherent flexibility of the catalytic zinc coordination shell in Thermolysin (TLN) and Histone Deacetylase 8 (HDAC8). We have observed different coordination modes and fast ligand exchange during the picosecond's time-scale. For TLN, the coordination of the carboxylate group of Glu166 to Zinc is found to continuously change between monodentate and bidentate manner dynamically; while for HDAC8, the flexibility mainly comes from the coordination to a non-amino-acid ligand. Such distinct dynamics in the zinc coordination shell between two enzymes suggests that the catalytic role of Zinc in TLN and HDAC8 is likely to be different in spite of the fact that both catalyze the hydrolysis of amide bond. Meanwhile, considering that such Born-Oppenheimer ab initio QM/MM MD simulations are very much desired but are widely considered to be too computationally expensive to be feasible, our current study demonstrates the viability and powerfulness of this state-of-the-art approach in simulating metalloenzymes.
锌配位的不同配位模式和快速配体交换被认为是锌离子的一个关键催化特性，这使其成为生物催化中一种非常重要的金属。然而，部分由于锌难以用光谱方法进行表征这一众所周知的困难，到目前为止，催化锌配位动态性质的证据主要是间接的。在这项工作中，采用了玻恩 - 奥本海默从头算量子力学/分子力学分子动力学模拟，它能够对金属活性位点的动力学进行第一性原理描述，同时恰当地考虑到异质且波动的蛋白质环境的影响。我们的模拟提供了关于嗜热菌蛋白酶（TLN）和组蛋白去乙酰化酶8（HDAC8）中催化锌配位壳固有灵活性的直接证据。我们在皮秒时间尺度上观察到了不同的配位模式和快速配体交换。对于TLN，发现Glu166的羧基与锌的配位在单齿和双齿方式之间动态地持续变化；而对于HDAC8，灵活性主要来自于与非氨基酸配体的配位。尽管这两种酶都催化酰胺键的水解，但两种酶的锌配位壳中这种明显的动力学差异表明锌在TLN和HDAC8中的催化作用可能不同。同时，鉴于这种玻恩 - 奥本海默从头算量子力学/分子力学分子动力学模拟非常必要，但人们普遍认为其计算成本过高而不可行，我们目前的研究证明了这种最先进的方法在模拟金属酶方面的可行性和强大功能。
