Harnessing the peptide code of bilingual biopolymers to control assembly and RNA localization

About This Grant

NON-TECHNICAL SUMMARY: Nucleic acids and proteins are both incredibly powerful in their ability to encode information and perform specific functions, yet they each benefit from unique advantages with regard to designability and breadth of function. To date, synthetic polymers seeking to mimic these natural biopolymers only take advantage of a single code – either nucleic acid or protein. The proposed work explores "bilingual biopolymers" as a novel class of biomolecules that are able to simultaneously encode both nucleic acid and protein information, in turn providing greater control over structure and function. Specifically, the research will explore modification of the protein code to control – in both time and space – the chemical properties of these functionalities, which will in turn provide control over assembly and other activities. We will explore methods that enable both rapid quantitative switching of the protein code as well as time-released activation. This will in turn expand the capabilities of these molecules toward applications in drug delivery and sensing. The ability to modify the protein code while also harnessing the nucleic acid code will be used to modulate the location of RNA in cells, enabling control over cellular function and potential therapeutic applications. This research project will span the fields of materials science, chemistry, and molecular biology, providing undergraduate and graduate students with a highly interdisciplinary training experience involving the use of cutting-edge techniques. This project will also contribute to public access to science through a science communication project implemented in a course taught by the PI, as well as through the PI’s participation in outreach activities including serving as a judge for both science fair and an online scientific poster session. TECHNICAL SUMMARY: "Bilingual biopolymers" are a novel class of programmable materials capable of interpreting both peptide and nucleic acid information codes to direct assembly, disassembly, and guest release. Peptide nucleic acid (PNA) serves as an ideal scaffold for these polymers, as it has a peptide-like backbone that can be functionalized with amino acid side chains and is able to bind sequence-specifically to DNA and RNA. In preliminary work, amphiphilic PNA sequences have been developed in which the amino acid code directs assembly and the nucleic acid code is targeted for stimuli-responsive disassembly. The current project is focused on controlling the assembly state through chemical modification of the amino acid side chains, which will enable exploration of applications for the peptide code beyond micelle assembly. Specifically, the proposed experiments will: (1) Establish the relationship between side chain modification and disassembly using photocleavable caging groups. (2) Develop tunable time-released control of assembly state using thermally-responsive 1,2-dicarbonyl amino acid caging groups. (3) Explore the use of bilingual PNA oligomers to direct RNA localization to biomolecular condensates in a sequence-specific way. Together, this work will enable the dual coding nature of these biopolymers to be harnessed to develop materials with potential for use in probing important biomedical questions as well as for therapeutics and cellular delivery. Additional broader impacts of the proposed research include activities aimed at improving undergraduate education and universal access to STEM research and scientific knowledge. 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.