SusChEM: Artificial Hydrogenases by Design: Hybrid Protein-Organometallic Catalysts

NSF 生命过程化学计划支持亚利桑那州立大学 Giovanna Ghirlanda 教授研究人工氢化酶设计的努力。 社会面临的紧迫挑战是可持续能源的开发。在这种背景下，如果能够开发出可扩展且环保的生产和利用方法，氢可能成为碳基燃料的清洁替代品。一种潜在的具有成本效益且对环境无害的制氢途径可以从自然界中收集，其中一系列称为氢化酶的特殊酶在温和条件下催化质子还原以及氢氧化，在活性位点使用铁等非贵金属。不幸的是，氢化酶是一种大型、复杂的蛋白质，具有多种缺点，阻碍了其在应用中的利用。 Ghirlanda 教授设计并优化了合成微型蛋白质，其中含有能够将质子还原为分子氢的人工有机金属位点。通过最先进的方法增强有机金属单元的存在，以优化蛋白质支架中的环境和长程相互作用，以获得良好的氢化酶活性。这种方法提供了一种测试天然氢化酶机制的方法，同时生成开发新型酶的蓝图。该项目依赖于高度跨学科的方法，为研究生和本科生提供丰富的现代生物无机化学培训。 Ghirlanda 博士与太阳能利用网络（一个学生领导的组织，在整个菲尼克斯地区的学校举办科学研讨会）合作，开发了教学模块，旨在遵守亚利桑那州六年级科学标准，并在课堂上引入与可持续能源相关的概念。仿生有机金属复合物阐明了质子还原的许多机制，但由于第二球和远程相互作用的结合受到限制，尚未达到天然氢化酶的效率。在这里，Ghirlanda 博士和她的团队研究了一种混合系统，通过该系统，简单、相对低效的有机金属中心的化学性质通过蛋白质支架提供的第二球和长程相互作用得以丰富。他们独特的策略是围绕使用非天然氨基酸来协调和稳定仿生有机金属催化剂。利用这种策略，小型肽模型系统在接近中性 pH 值的水中可以产生新生的氢气。该项目现在（1）扩展了合成方法来制备一系列人工氨基酸，（2）开发了从头设计的人工氢化酶原型，（3）使用计算蛋白质设计与定向方法相结合来优化第二配位层和长程相互作用。开发能够以可持续方式生产燃料的可进化蛋白质混合催化剂直接解决了全球的紧迫需求。除了氢气生产之外，该项目还建立了开发混合催化剂的程序，该催化剂可广泛适用于各种化学反应，包括那些自然界中不发生的反应，并有可能影响高价值化学品的生产。

The NSF Chemistry of Life Processes Program supports the efforts of Professor Giovanna Ghirlanda of Arizona State University to investigate the design of artificial hydrogenases. A pressing challenge facing society is the development of sustainable energy sources. In this context, hydrogen emerges as a possible clean alternative to carbon-based fuels, if scalable and environmentally friendly methods for its production and utilization can be developed. A potentially cost-effective and environmentally sound route to hydrogen can be gleaned from nature where a family of specialized enzymes called hydrogenases catalyzes proton reduction as well as hydrogen oxidation under mild conditions, using non-precious metals such as iron at the active site. Unfortunately, hydrogenases are large, complex proteins with several drawbacks that prevent their utilization in applications. Professor Ghirlanda designs and optimizes synthetic miniaturized proteins that contain artificial organometallic sites that are capable of proton reduction to molecular hydrogen. The presence of the organometallic unit is augmented with state-of-the-art methods to optimize the environment and long-range interactions in the protein scaffold, in an effort to obtain good rates of hydrogenase activity. This approach provides a means to test natural hydrogenase mechanisms while generating blueprints to develop novel enzymes. The project relies on a highly interdisciplinary approach that offers students at the graduate and undergraduate level a rich training in modern bioinorganic chemistry. In partnership with the Solar Utilization Network (a student-led organization that conducts science workshops in schools throughout the Phoenix area), Dr. Ghirlanda develops teaching modules designed to adhere to the Arizona sixth grade science standards and to introduce concepts related to sustainable energy in the classrooms.Bioinspired organometallic complexes have clarified many mechanistic aspects of proton reduction, but have not reached the efficiency of natural hydrogenases due to limitations on the incorporation of second-sphere and long-range interactions. Here, Dr. Ghirlanda and her group examine a hybrid system by which the chemistry of simple, relatively inefficient organometallic centers are enriched through second-sphere and long-range interactions provided by a protein scaffold. Their unique strategy is built around the use of unnatural amino acids that can coordinate and stabilize bioinspired organometallic catalysts. Using this strategy, nascent hydrogen production by small peptide-based model systems in water at near-neutral pH have been demonstrated. This project now (1) expands synthetic methodologies to prepare a family of artificial amino acids, (2) develops prototype de novo-designed artificial hydrogenases, and (3) uses computational protein design concomitantly with directed methods to optimize second coordination sphere and long range interactions. The development of evolvable protein-based hybrid catalysts capable of producing fuel in a sustainable manner directly addresses an urgent global need. Beyond hydrogen production, this project establishes a procedure to develop hybrid catalysts that may be widely applicable to a variety of chemical reactions, including those not occurring in nature, with the potential to impact the production of high-value chemicals.