开发一套用于计算生物化学中量子同位素效应的公用程序包

Isotope quantum effects play a crucial role in determining reaction mechanisms in protein and RNA catalysis. This is because oftentimes in biocatalysis, it is straightforward to find the stable reactant and product states in thermal equilibrium. Yet, every possible reaction path connecting the reactant and product states is characterized by its own rate-limiting transition state, which, by its nature, is unstable, and thus is very hard to be captured in experiment. On the other hand, isotope quantum effects on biochemical reactions are very sensitive to the rate-limiting transition state. Therefore, measuring the values of isotope quantum effects have always been considered as a (most) direct probe of rate-limiting transition state in experiment. Nevertheless, such important experimental numerical values or probe actually cannot directly tell us what the structure of the rate-limiting transition state really is. As a result, people usually would seek for help from calculations of isotope quantum effects and computational visualization as complementary approach to experiment for identifying the structure of the rate-limiting transition state. In order to accurately compute the isotope quantum effects, using Feynman's path integral formulation has been proven to be a robust choice. In particular, we (KYW) have already developed an automated integration-free path-integral (AIF-PI) method. Using our AIF-PI method, we have successfully determined the molecular structures of the rate-limiting transition states for a series of proton-transfer reactions and RNA transphosphorylation reactions, which were published in J. Am. Chem. Soc. (Impact Factor: 9.9) and Angew. Chem. Int. Ed. (cover image; Impact Factor: 13.5), respectively. Due to the great impacts that have already been given to the community in biocatalysis of protein and RNA molecules, it is absolutely important for us to create a public-access program package that makes use of our AIF-PI method to economically and accurately calculate the isotope quantum effects on biochemical reactions (so far it was only preliminarily implemented on Mathematica). Eventually the public-access software would become an essential computational tool as a "black box" for experimentalists to determine the molecular structure of the rate-limiting transition state, right after the isotope effects are measured.

量子同位素效应在决定蛋白质和RNA催化作用的机理中扮演关键角色。这因连接反应态和产物态的每一条可能的反应路径是以各自的限速过渡态来表征。过渡态是不稳定，实验难俘获。 然而同位素效应对限速过渡态非常的敏感。其实验值被视为探测限速过渡态的(最)直接方法。 但这探测法不能直接地告诉过渡态分子结构。人们用计算和显像方法，补充实验不足，来确定其结构。 这方面我已开发一种路径积分方法(AIF-PI)，并在质子转移[J.Am.Chem.Soc.论文,影响因子9.9]和RNA转磷酸[Angew.Chem.Int.Ed.封面论文,影响因子13.5)]反应中计算同位素效应和确定了限速过渡态分子结构。 因此开发一套公用程序包以应用我们的AIF-PI是很重要(目前仅在Mathematica中初步执行)。这将成为实验者不可少的工具；测量同位素效应后，用这类似"黑匣子"的程序包就可得悉限速过渡态的分子结构。

开发一套用于计算生物化学中量子同位素效应的公用程序包的一个必须部分是需要有一个共享内存密集型高性能的工作站计算机。..这青年科学基金项目的首批研究资金只有RMB 150,000元。因此，我们需要等待第二次次批出的剩余资金（RMB 100,000元），才能获得足够的资金（～RMB 200,000元）去购买该必须的共享内存密集型高性能的工作站计算机。..我们终于在2015年十月份买了这个内存密集型高性能的工作站计算机。在2016年近三月份时间可以安装并用得上。..然而，其间我们已经发表了四篇期刊论文。全都是关于计算生物化学中量子同位素效应，和关于我们用来计算量子同位素效应的理论方法。这理论方法就是我们最近开发的费曼路径积分方法。..通过这四篇期刊论文的研究课题，我自己的研究小组成员都得到了很好的训练去应对更具挑战性的研究课题，包括继续去完成正在开发中的一套用于计算生物化学中量子同位素效应的公用程序包。我亦成功培养了有一位博士毕业生。