INSPIRE: Mimicking the Functional Complexity of Biology with Man-Made Systems

CREATIV奖的部分资金来自生物科学局分子和细胞生物科学部的生物分子动力学、结构和功能群；数学和物理科学局化学部的生命系统物理计划和生命过程化学计划；以及工程局化学、生物工程、环境和运输系统部的生物工程和工程保健群。该CREATIV项目的目标是将功能部件组织成询问和控制生物系统的设备或接口。生物学使用线性杂聚体进行非常复杂的过程，线性杂聚体是通过将相对较小的一组单体按特定顺序连接在一起而制成的。这种相当数字化的方法来创建化学功能，原则上可以应用于我们自己创造的分子尺度设备的开发。然而，到目前为止，已经使用了不能单独检测或计算设计的分子库。此外，将功能成分组织到这样的设备中或创建结构化的分子界面的能力已经相当原始。然而，最近，一些跨学科的技术结合在一起，有望提供真正新的方法来创造可与生物学相媲美的化学复杂性和分子功能。已经开发出专门设计、制造和询问有序文库中数百万不同分子的方法。此外，功能元件可以以纳米精度集成到分子规模的设备中，或者直接与微电子设备连接，从而允许对复杂的化学和生物系统进行询问和控制。在这里，我们提出了利用这些能力的综合力量的第一步。最初，将在具有接近哺乳动物免疫系统的分子识别能力的表面上创建多价合成配体的有序库。然后，这个文库将被用来加强三项研究工作：利用DNA纳米结构组织和优化多酶反应途径；以细菌光合作用反应中心为模型将氧化还原蛋白质与电极连接；最终识别真核细胞类型，并通过特定的分子相互作用控制它们的基因表达模式和生长/分化特征。计算设计、高通量分子合成、高通量详细化学分析和电子集成方面的技术和概念的集成有可能创造出具有生物系统的复杂性和多样化功能的完全人工系统，但具有与电子世界无缝连接的可访问的控制机制。该项目依赖于计算、合成、电子和生物监管能力之间的合作。该项目将使初级科学家面临跨学科研究的挑战，并将使他们能够参与创建概念框架和初始工具，这些概念框架和初始工具可能导致高效的多酶途径、个性化药物开发的快速系统、综合诊断、能量收集以及一种新型的将化学和电子信息相互转换的生物杂交电路。

This CREATIV award is partially funded by the Biomolecular Dynamics, Structure and Function Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences; the Physics of Living Systems Program in the Division of Physics and the Chemistry of Life Processes Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences; and the Bioengineering and Engineering Healthcare Cluster in the Division of Chemical, Bioengineering, Environmental and Transport Systems in the Directorate of Engineering. The objective of this CREATIV project is to organize functional components into devices or interfaces that interrogate and control biological systems. Biology performs very complex processes using linear heteropolymers that are made by hooking together a relatively small set of monomers in a particular order. This rather digital approach to creating chemical function can, in principle, be applied to the development of molecular scale devices of our own creation. However, thus far, libraries of molecules that cannot be individually assayed or computationally designed have been used. In addition, the ability to organize functional components into such devices or to create structured molecular interfaces has been quite primitive. Recently, however, a number of interdisciplinary technologies have come together which promise to provide truly new approaches to creating chemical complexity and molecular function that rivals that of biology. Methods have been developed to specifically design, fabricate, and interrogate millions of different molecules in ordered libraries. In addition, functional elements can be incorporated into molecular-scale devices with nanometer accuracy or interfaced directly with micro-electronics, allowing both interrogation and control of complex chemical and biological systems. Here, the first step towards capitalizing on the combined power of these capabilities is proposed. Initially an ordered library of multivalent synthetic ligands on a surface that has a molecular recognition capacity approaching that of the mammalian immune system will be created. This library will then be used to enhance three research efforts; organizing and optimizing multienzyme reaction pathways using DNA nanostructures; interfacing redox proteins with electrodes using the bacterial photosynthetic reaction center as a model; and finally identifying eukaryotic cell types and controlling their gene expression patterns and growth/differentiation characteristics via specific molecular interactions.The integration of technologies and concepts in computational design, high throughput molecular synthesis, high throughput detailed chemical analysis, and electronic integration has the potential to create completely artificial systems with the complexity and diverse functionality of biological systems, but with the accessible control mechanisms that interface seamlessly with the electronic world. The project depends on collaboration among computational, synthetic, electronic and biological regulation capabilities. This project will expose junior scientists to the challenges of interdisciplinary research, and will allow them to be involved at the creation of conceptual frameworks and initial tools that could lead to highly efficient multi-enzyme pathways, rapid systems for personalized drug development, comprehensive diagnostics, energy harvesting, and a new type of biohybrid circuitry that interconverts chemical and electronic information.