Greasing Protein Wheels—Harnessing Post-Translational Lipidation for Bioinspired Materials Science and Engineering

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, proteins still lack the chemical diversity of their synthetic analogues due to the limited repertoire of canonical amino acids. This limitation 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.<br/><br/>Our focus is to reprogram PTMs to synthesize <i>de novo</i> designed hybrid biopolymers with programmable self-assembly. In this talk, I will discuss our recent work on leveraging post-translational lipidation to create genetically encoded amphiphiles with temperature-programmable assembly. Though the chemical biology of lipidation is under intense investigation, protein lipidation remains a major, untapped resource in our synthetic, biomaterials, and therapeutic toolkit. 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 that facilitates their production to study their materials properties.<br/><br/>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 “<i>molecular syntax”</i> will enable the development of the next generation of biomaterials and therapeutics that rival the exquisite hierarchy and capabilities of biological systems.