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

美国国家科学基金会生命过程化学项目支持亚利桑那州立大学Giovanna Ghirlanda教授对人工氢化酶设计的研究。社会面临的一个紧迫挑战是可持续能源的发展。在这种情况下，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。一种具有潜在成本效益且环保的制氢途径可以从自然界中收集到，在温和条件下，一种称为氢化酶的特殊酶家族可以催化质子还原和氢氧化，在活性位点使用非贵金属（如铁）。不幸的是，氢化酶是大而复杂的蛋白质，有一些缺点阻碍了它们的应用。Ghirlanda教授设计并优化了含有能够将质子还原为氢分子的人工有机金属位点的合成小型化蛋白质。有机金属单元的存在通过最先进的方法来优化环境和蛋白质支架中的远程相互作用，以努力获得良好的氢化酶活性率。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。该项目采用高度跨学科的方法，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。在与太阳能利用网络（一个学生主导的组织，在整个凤凰城地区的学校举办科学研讨会）的合作中，Ghirlanda博士开发了教学模块，旨在坚持亚利桑那州六年级的科学标准，并在教室中引入与可持续能源相关的概念。生物激发的有机金属配合物已经阐明了质子还原的许多机制方面，但由于第二球和远程相互作用的限制，还没有达到天然氢化酶的效率。在这里，吉兰达博士和她的团队研究了一个混合系统，在这个系统中，简单的、相对低效的有机金属中心的化学成分通过蛋白质支架提供的第二球体和远程相互作用得到了丰富。他们独特的策略是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激发的有机金属催化剂。利用这一策略，在接近中性pH值的水中，小的基于肽的模型系统已经证明了新生的氢生产。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)开发了全新设计的人工氢化酶原型；(3)使用计算蛋白质设计结合定向方法优化第二配位球和远程相互作用。开发可进化的蛋白质基混合催化剂，使其能够以可持续的方式生产燃料，直接解决了全球迫切的需求。除了制氢之外，该项目还建立了一种开发混合催化剂的程序，这种催化剂可能广泛适用于各种化学反应，包括那些不发生在自然界中的化学反应，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.