International Collaboration in Chemistry: Protein Dynamics and Heme Protein Function

生命过程化学（CLP）项目的这一奖项支持阿尔伯特·爱因斯坦医学院的Denis Rousseau教授和syn - ru Yeh教授对两种酶系统（一氧化氮合酶和吲哚胺双加氧酶）催化机制的能源格局进行基础研究。这项研究将作为国际化学合作（ICC）的一部分，与德国卡尔斯鲁厄大学的Uli Nienhaus教授合作，他的工作将得到德国研究委员会（DFG）的支持。一氧化氮合酶催化l -精氨酸和氧形成信号分子一氧化氮；吲哚胺双加氧酶通过将l -色氨酸氧化为n -甲酰基尿氨酸来调节免疫反应。为了确定调节这两种蛋白质酶促反应能量景观的动力学性质，将对关键氨基酸残基进行突变，并在平衡和动力学条件下通过光谱方法研究其结构和催化性质。突变体将被送到位于卡尔斯鲁厄的Nienhaus实验室，通过温度导数傅立叶变换红外光谱进行动力学测量；由此产生的数据将与阿尔伯特·爱因斯坦医学院获得的基本结构和功能特性进行比较。这个过程将不断重复，直到对这两种酶的动力学作用有了全面的了解。为了获得催化机理的良好基础，将采用量子力学和分子力学相结合的计算方法对数据进行整合。合作将包括两个小组访问彼此的实验室，以制定研究策略并评估研究结果。这些美国和德国团体之间的访问将为参与该项目的所有学生和博士后提供优秀的培训机会。该研究将揭示每种酶的分子动力学如何决定其功能特性，从而为开发这些酶的治疗靶点奠定基础。

This award in the Chemistry of Life Processes (CLP) program supports work by Professors Denis Rousseau and Syun-Ru Yeh at the Albert Einstein College of Medicine to carry out fundamental studies on the energy landscape that underlies the catalytic mechanism of two enzyme systems: nitric oxide synthase and indolamine dioxygenase. This research will be done as part of an International Collaboration in Chemistry (ICC) with Professor Uli Nienhaus at the University of Karlsruhe in Germany, whose work will be supported by the Deutsche Forschungsgemeinschaft (DFG). Nitric oxide synthase catalyzes the formation of the signaling molecule, nitric oxide, from L-arginine and oxygen; and indolamine dioxygenase regulates immune responses by oxidizing L-tryptophan to N-formylkynurenine. To determine the dynamic properties that modulate the energy landscapes of the enzymatic reactions of these two proteins, critical amino acid residues will be mutated and their structural and catalytic properties will be the studied by spectroscopic methods under equilibrium and kinetic conditions. The mutants will be sent to the Nienhaus lab in Karlsruhe for the dynamics measurements by temperature derivative Fourier transform infrared spectroscopy; the data thus generated will be compared to the basic structural and functional properties obtained at the Albert Einstein College of Medicine. The process will be repeated until a comprehensive understanding of the role of dynamics in these two enzymes is achieved. In order to obtain a sound foundation of the catalytic mechanisms, the data will be integrated by combined quantum mechanics and molecular mechanics calculations.The collaboration will include visits by both groups to each other's lab to set the strategy for the research and evaluate the findings. These visits between the US and German groups will provide outstanding training opportunities to all of the students and postdoctoral fellows participating in this project. The research will reveal how the molecular dynamics of each enzyme dictate its functional properties and will therefore serve as a foundation for the development of therapeutic targets for these enzymes.