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

NSF生命过程化学项目支持亚利桑那州立大学Giovanna Ghirlanda教授研究人工氢酶的设计。社会面临的一个紧迫挑战是发展可持续能源。在这种情况下，如果能够开发出可扩展和环境友好的氢气生产和利用方法，氢气可能成为碳基燃料的清洁替代品。从自然界中可以获得一种潜在的成本效益和环境友好的氢气途径，在温和的条件下，一种名为氢酶的特殊酶家族利用活性中心的铁等非贵金属催化质子还原和氢氧化。不幸的是，氢酶是一种大的、复杂的蛋白质，有几个缺点阻碍了它们的应用。吉兰达教授设计并优化了合成的微型蛋白质，这种蛋白质含有能够将质子还原为分子氢的人造有机金属位置。有机金属单元的存在被最先进的方法增强，以优化蛋白质支架中的环境和远程相互作用，以努力获得良好的氢酶活性。这种方法提供了一种测试自然氢酶机制的方法，同时生成开发新酶的蓝图。该项目依赖于一种高度跨学科的方法，为研究生和本科生提供现代生物无机化学方面的丰富培训。Ghirlanda博士与太阳能利用网络(一家由学生主导的组织，在凤凰城地区的所有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的科学标准，并在课堂上介绍与可持续能源相关的概念。生物启发的有机金属络合物阐明了质子还原的许多机理方面，但由于第二球和远程相互作用的限制，尚未达到天然氢酶的效率。在这里，吉兰达博士和她的团队研究了一种混合系统，通过蛋白质支架提供的第二球和远程相互作用，丰富了简单、相对低效的有机金属中心的化学成分。他们独特的策略建立在使用非天然氨基酸的基础上，这种氨基酸可以协调和稳定生物启发的有机金属催化剂。利用这一策略，已经证明了在近中性的pH条件下，基于小肽的模型系统在水中产生新生氢气。该项目现在(1)扩展了合成方法以制备一系列人工氨基酸，(2)开发了重新设计的人工氢酶原型，(3)结合使用计算蛋白质设计和定向方法来优化第二配位球和远程相互作用。能够以可持续的方式生产燃料的可进化蛋白质基混合催化剂的开发直接满足了全球的迫切需求。除制氢外，该项目还建立了一种程序，以开发可广泛适用于各种化学反应的混合催化剂，包括那些可能影响高价值化学品生产的化学反应。

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.