(235b) Greasing Proteins Wheels: Genetically Encoded Amphiphiles with Programmable Architecture and Assembly

Advances in recombinant DNA technology have expanded our ability to design and produce protein-based materials with superior control over the biomacromolecule's length, sequence, and structure. Despite these positive attributes, the limited repertoire of canonical amino acids restricts the available chemical design space (and thus the function) of protein-based biomaterials. In our quest to overcome this evolutionary constraint, we are inspired by a solution offered by Nature: leveraging specific chemical transformations to modify proteins with non-proteinogenic building blocks, a process called post-translational modification (PTM), which expands the chemical diversity of the proteome by more than two orders of magnitude. Our focus is to reprogram PTMs to synthesize de novo designed hybrid biopolymers with programmable self-assembly.

In this talk, I will discuss our recent work to use post-translational lipidation to create genetically encoded amphiphiles with temperature-programmable assembly. Facile, scalable, and inexpensive lipidation of proteins is currently an unmet synthetic capability. Lipidated proteins cannot be produced by genetic code expansion methods due to the stringent preference of ribosomes for amino acid-derived motifs. Alternatively, their multi-step convergent semi-synthesis is laborious and technically challenging. To address these challenges, we have developed operationally simple, high yield biosynthetic routes for the production of lipidated proteins to generate both canonical and non-canonical lipidated proteins —i.e., with lipid, protein, and lipidation sites not found in nature—at quantities sufficient for materials and biomedical applications.

I will demonstrate that the effect of lipidation on the assembly, nano-morphology, and material properties of lipidated proteins diverges significantly from experimental results and theoretical predictions of structurally related materials such as amphiphilic polymers and peptide-amphiphiles. Our working hypothesis is that the "molecular syntax" of lipidated proteins encodes for interactions that are absent in synthetic polymers and short peptides. Specifically, the large molecular surface of lipids enables them to contact multiple segments of peptide chains, and these nonnative interactions synergize/interfere with the ability of proteins to fold, resulting in distinctive functional consequences. Revealing this molecular syntax will enable the development of the next-generation biomaterials and therapeutics that rival the exquisite hierarchy and capabilities of biological systems.