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

美国国家科学基金会生命过程化学计划支持亚利桑那州立大学的乔万娜·吉兰达教授研究人工氢化酶的设计。 社会面临的一个紧迫挑战是开发可持续能源。在这种情况下，氢作为碳基燃料的可能的清洁替代品出现，如果可以开发其生产和利用的可扩展和环境友好的方法。一种潜在的具有成本效益和环境友好型的制氢途径可以从自然界中收集，其中一种称为氢化酶的专门酶家族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，氢化酶是大的、复杂的蛋白质，具有阻止其在应用中利用的几个缺点。Ghirlanda教授设计并优化了合成的微型蛋白质，这些蛋白质含有能够将质子还原为分子氢的人工有机金属位点。有机金属单元的存在用最先进的方法来增强，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速率。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现代生物无机化学的丰富培训。与太阳能利用网络合作（一个学生主导的组织，在整个凤凰城地区的学校进行科学研讨会），博士. Ghirlanda开发的教学模块，旨在坚持亚利桑那州六年级的科学标准，并介绍有关可持续能源的概念在课堂上.生物启发的有机金属配合物已经澄清了质子还原的许多机械方面，但是由于第二球和长程相互作用的结合的限制，还没有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物质通过蛋白质支架提供的第二球体和长程相互作用而富集。他们独特的策略是围绕使用非天然氨基酸，可以协调和稳定生物启发的有机金属催化剂。使用这种策略，已经证明了在近中性pH的水中通过基于小肽的模型系统的新生氢产生。该项目现在（1）扩展合成方法以制备一系列人工氨基酸，（2）开发新设计的人工氢化酶原型，（3）使用计算蛋白质设计伴随定向方法来优化第二配位球和长程相互作用。能够以可持续的方式生产燃料的可进化的基于蛋白质的混合催化剂的开发直接解决了全球的迫切需求。除了制氢之外，该项目还建立了一个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，包括那些在自然界中不发生的化学反应，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.