CAREER: Modular Protein Origami to Build Genetically Programmable Biomaterials

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PART 1: NON-TECHNICAL SUMMARYNature builds biological materials at the scale of nanometers that perform essential functions for life. Like the paper-folding artwork known as origami, biological molecules such as proteins fold and assemble into small-scale materials in various shapes. The evolution of life for billions of years has developed this sophisticated method to build remarkably precise and tiny materials in every living system. However, understanding nature’s way and exploiting it to build artificial materials that can program various biological functionalities is not yet close to realization. This project aims to understand how a class of short, modular helical protein tools, called coiled-coils, fold and interact with each other and make molecular origami using the protein tools to create nanometer-scale biomaterials. The principal investigator integrates research and education efforts to study the interactions between the coiled-coil proteins and their folding into origami shapes. Protein origami can be used to develop biomaterials with programmable complex functionalities, which can enable unprecedented technologies to solve problems in biology and medicine and contribute to the advancement in biomanufacturing and healthcare. Genetic manipulations of microorganisms are utilized to generate protein origami materials, followed by revealing their shapes and functions using biophysical characterization and computational tools. Education modules and outreach activities, in partnership with university workshops, are created to generate interest in protein materials and engage students of all levels, with a focus on how to design and make protein origami. Research integration activities provide lab experiences to assist the training of undergraduate and graduate students, including women in engineering and historically underrepresented students.PART 2: TECHNICAL SUMMARYThis project aims to understand the programmable protein assembly in complex systems, termed modular protein origami, and to build a robust framework for the design of biological nanomaterials with customizable sizes, shapes, and genetically programmable functionalities. Coiled-coil protein motifs that serve as versatile and modular toolkits with specific, controllable, and orthogonal protein-protein interactions are used to create well-defined protein origami nanostructures that perform biological functions. The principal investigator integrates research and education efforts to gain a comprehensive understanding of (i) the interaction modularity of coiled-coil proteins arranged in complex origami topologies, (ii) how the protein origami is controlled and used to program functionalities in cells, and (iii) genetic programmability of microbial assembly through modular protein origami on cell surfaces. To accomplish the objectives, experimental techniques for recombinant protein synthesis as well as protein characterization tools such as small-angle scattering and fluorescent microscopy are utilized in combination with computational structure modeling techniques. The outcome fills the critical knowledge gap in designing biofunctional protein nanomaterials using the coiled-coil protein motifs for technology development in fields ranging from synthetic biology to medicine. The education modules and outreach activities offer students in chemical engineering exposure to the basics of protein material design and engineering as well as techniques for protein synthesis, modeling, and characterization. The activities engage underrepresented engineering students and K-12 students in the neighboring community with a focus on hands-on experiences in protein origami design and fabrication.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.