Research Starter Grant: Integrated Protein Design for Non-natural Electron-Transfer Systems

生命与电子转移（ET）的过程密不可分。ET反应是生物能量过程的核心，如制氢、光合作用和细胞呼吸。生命体中的ET类似于为家用电器供电的电流，因为必须有一个电子源（插座）和电流的路径，以便为电气设备提供能量，使其能够工作。理解和控制电子转移过程中涉及的生物机制（即来源和途径）的能力将允许开发可用于造福社会的微观电子设备。与对自然现象中电子转移（ET）的一般理解相反，基于蛋白质的ET系统的表达设计-即，将促进生物医学和生物工业应用的高阶设备的生产的元素-提出了一个重大挑战。为了解决这一缺陷，假设必须将核心理论方法（经典ET理论）与现有的蛋白质设计程序相结合，以创建具有定制功能的ET系统。本研究的总体目标是扩大对生物系统中电子转移的一般特征的理解，并为设计et功能生物分子提供基本框架。为了实现这一目标，将采用实验和计算方法相结合的理论方法。这种综合的多学科框架将用于生产能够与自然发生的功能元素和非自然材料相互作用的单一合成材料。这种相互作用的动态范围将促进一系列新颖和有用的界面，能够在分子水平上进行有意义的交流和逻辑操作。同样，生产可行的生物电子学的能力将推进对基本生命过程的理解，并扩大设计生物分子作为高级功能设备（例如，基于生物材料的电子电路，使用体内天然物质产生能量的生物燃料电池，为可植入设备提供动力，以及先进的假肢）的构建块的使用。更广泛的影响本研究项目将提供一个有益的、鼓励的和富有成效的研究环境，使研究方法和科学成果能够以一种支持性和建设性的方式进行批判性评估，从而促进成功的科学同行的发展。该项目还将大力鼓励和支持未被充分代表的研究生、本科生和职业高中学生参与研究。有抱负的科学家参加这个项目将受益于非常独特的机会，在实验和计算方法方面接受同等的培训。此外，这项研究将通过(i)广泛的合作和（ii）通过新的跨学科课程模块将这项研究整合到耶鲁大学的本科和研究生课程中，从而增强我们目前的研究和教育基础设施。

Intellectual MeritLife is inextricably linked to a process called electron-transfer (ET). ET reactions are central to bioenergetic processes, such as hydrogen production, photosynthesis, and cellular respiration. ET in living organisms is analogous to an electrical current that powers a household appliance in that there must be a source of electrons (an outlet) and a pathway for the current to follow in order to supply energy to the electrical device so that it is able to function. The ability to understand and control biological machinery - i.e., the source and pathways - involved in the process of electron-transfer will allow the development of microscopic electronic devices that could be used to benefit society. Contrary to the general understanding of electron-transfer (ET) in naturally occurring phenomena, the express design of protein-based ET systems - i.e., elements that will facilitate the production of higher-order devices for biomedical and bio-industrial applications - presents a significant challenge. To resolve this deficiency, it is hypothesized that a central theoretical approach (classical ET theory) must be integrated with existing protein design procedures to create ET systems with tailored functions. The overarching goal of this research is to expand the understanding of general features of electron-transfer in biological systems as well as to generate the fundamental framework for the design of ET-functional biomolecules. To accomplish this, a combination of experimental and computational approaches, informed by theory, will be employed. This integrated multi-disciplinary framework will be used to produce singular synthetic material capable of interacting with naturally occurring functional elements and non-natural materials alike. This dynamic range of interactions will facilitate an array of novel and useful interfaces capable of meaningful communication and logical operations at the molecular level. Likewise, the ability to produce viable bioelectronics will advance the understanding of fundamental life processes and expand the use of designed biomolecules as the building blocks of higher-level functional devices (e.g., biomaterial-based electronic circuitry, biofuel cells that use natural substances in the body to generate energy to power implantable devices, and advanced prosthetics).Broader ImpactThis research project will facilitate the development of successful scientific peers by providing a helpful, encouraging, and productive research environment in which research methods and scientific output can be critically evaluated in a supportive and constructive manner. This project will also strongly encourage and support the participation of underrepresented graduate, undergraduate, and career high school students in research. Aspiring scientists that participate in this program will benefit from the very unique opportunity to receive equal training in experimental and computational approaches. Moreover, this research will enhance our current infrastructure for research and education through (i) extensive collaborations and (ii) integration of this research into the Yale undergraduate and graduate curricula via new interdisciplinary course modules.