RUI: Study of Small Molecule Activation by Molybdenum Enzymes using Computational Methods

惠特曼学院的Dalia Rokhsana得到了化学系生命过程化学项目的支持，该奖项旨在研究基于钼的酶的反应性，这种酶是一种细菌蛋白质，可以催化水分解反应产生氢气。氢是燃料电池、推进系统和内燃机的重要绿色能源。Rokhsana和她的团队正在使用最先进的计算化学和分子建模技术来了解蛋白质活性部位如何控制结构、功能、特异性和反应性。该研究对大规模氢气生产的仿生设计和优化具有潜在的应用价值。该项目正在支持这所以本科生为主的院校的本科生参与。这些学生共同撰写科学论文，并在国家会议和地区会议上发表演讲。与领先的计算科学家的外部合作加强了科学发现与学生教育的整合，与惠特曼学院推广的教师-学者模式保持一致。基于这项研究的问题与计算化学和生物化学的课程作业相结合。生物系统的一项化学功能是在环境条件下激活惰性小分子。了解这些过程的分子机制是生物学和化学交界处的一个具有挑战性的领域。在这个项目中，Rokhsana和她的团队专注于一种不同的钼酶家族，这些酶催化氧转移来相互转化不同的底物(一氧化碳、亚硫酸盐、亚砷酸盐等)。同时将水分解成质子和电子。这项研究集中在一个鲜为人知的双金属[钼-S-铜]活性中心的钼酶，一氧化碳脱氢酶。第一个目标是研究活性中心的组成作为氧化还原、自旋和质子化状态的函数。第二个目标是表征一氧化碳不可逆催化转化为二氧化碳过程中中间体和过渡态的几何和电子结构。由于缺乏关于实验中间体的直接和明确的信息，计算方法是必要的。Rokhsana和她的团队正在利用现实量子力学(QM)和扩展量子力学/分子力学(QM/MM)模型来系统和全面地研究蛋白质环境对活性中心几何结构和电子结构的影响，并了解内部配位球和外部蛋白质环境如何控制和调节金属酶的功能。这项工作可能会为深入了解CO氧化的整体催化机理，并将其应用于水分解反应的仿生体系的分子工程提供参考。该项目让本科生沉浸在全面和互补的生物无机和计算化学研究中，涉及最先进的建模和模拟技术。新课程有助于满足惠特曼学院学生对研究机会的巨大需求，并促进与更广泛的化学界的新合作和参与。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Dalia Rokhsana of Whitman College is supported by an award from the Chemistry of Life Processes Program in the Division of Chemistry to investigate the reactivity of molybdenum-based enzymes, bacterial proteins that catalyze water-splitting reactions to produce hydrogen gas. Hydrogen is an important "green" energy source for fuel cells, propulsion systems, and combustion engines. Rokhsana and her group are using state-of-the-art computational chemistry and molecular modeling techniques to understand how the protein active site controls structure, function, specificity, and reactivity. This research has potential applications to the biomimetic design and optimization of large-scale hydrogen gas production. The project is supporting undergraduate student engagement at this primarily undergraduate institution. These students co-author scientific papers, and make presentations at national meetings and regional conferences. External collaborations with leading computational scientists enhance the integration of scientific discovery with student education, in keeping with the teacher-scholar model promoted at Whitman College. Problems based on the research are integrated with coursework in computational chemistry and biochemistry. One chemical functions of biological systems is the activation of inert small molecules under ambient conditions. Understanding the molecular mechanism of these processes is a challenging areas at the interface of biology and chemistry. In this project, Rokhsana and her group are focusing on a diverse family of molybdenum enzymes that catalyze oxo-transfer to interconvert various substrates (carbon monoxide, sulfite, arsenite, etc.) into products, while splitting water into protons and electrons. This research focuses on a poorly-understood bimetallic [Mo-S-Cu] active site of a Mo-enzyme, CO dehydrogenase. The first aim is to investigate the composition of the active site as a function of redox-, spin-, and protonation-states. The second aim is to characterize geometric and electronic structures of intermediates and transition states during the non-reversible, catalytic transformation of carbon monoxide into carbon dioxide. A computational approach is necessary due to the lack of direct and unambiguous information about intermediates from experiments. Rokhsana and her group are utilizing realistic quantum mechanical (QM) and extended quantum mechanical/molecular mechanical (QM/MM) models to systematically and comprehensively investigate the effect of protein environment on the geometric and electronic structure of the active site, and understand how the inner coordination sphere and outer protein environment control and tune metalloenzyme function. This work may providing insights into the overall catalytic mechanism of CO oxidation, with application to molecular engineering of biomimetic systems for the water splitting reaction. The project is immersing undergraduate students in comprehensive and complementary bioinorganic and computational chemistry research involving state-of-the-art modeling and simulation techniques. The new course is helping meet the considerable demand for research opportunities requested by students at Whitman College, and facilitating new collaborations and engagement with the broader chemistry community.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.