Join us to hear from Davoud Mozhdehi about his research at Syracuse University!

Abstract: Recent advances in recombinant DNA technology have enabled the precise design and production of protein-based materials, offering unprecedented control over their composition, structure, and function. Yet, the limited repertoire of canonical amino acids restricts the chemical diversity—and thus the functionality—of these biomaterials. To address this limitation, we draw inspiration from 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. Motivated by this bioinspired strategy, my lab focuses on leveraging protein lipidation to create de novo hybrid biopolymers with programmable structure and function. Although the chemical biology of lipidation has garnered intense interest, methods for producing lipidated proteins in a scalable, cost-effective manner remain scarce. Conventional approaches are hindered by the ribosome’s strict preference for amino acid-derived motifs or by labor-intensive and technically challenging semi-synthetic routes. ribosome’s strict preference for amino acid-derived motifs or by labor-intensive and technically challenging semi-synthetic routes.
To overcome these hurdles, we have developed high-yield biosynthetic methods for producing lipidated proteins, enabling systematic investigation of their structure and properties. Our findings reveal that the nano-assembly and liquid–liquid phase separation behaviors of lipidated proteins diverge markedly from predictions based on synthetic polymeric surfactants or peptide–amphiphiles. Although lipid moieties represent only a small fraction of the overall molecular mass, their pronounced hydrophobicity significantly alters protein hydration and inter-domain interactions, exerting effects that extend well beyond the site of modification. Understanding this “molecular syntax” will pave the way to next-generation biomaterials and therapeutics capable of mirroring the sophisticated hierarchy and functionality observed in living systems.
 

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