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

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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.