Abstract
Biology utilizes multiple strategies, including sequestration in lipid vesicles, to raise the rate and specificity of chemical reactions through increases in effective molarity of reactants. We show that micelle-assisted reaction can facilitate native chemical ligations (NCLs) between a peptide-thioester – in which the thioester leaving group contains a lipid-like alkyl chain – and a Cys-peptide modified by a lipid-like moiety. Hydrophobic lipid modification of each peptide segment promotes the formation of mixed micelles, bringing the reacting peptides into close proximity and increasing the reaction rate. The approach enables the rapid synthesis of polypeptides using low concentrations of reactants without the need for thiol catalysts. After NCL, the lipid moiety is removed to yield an unmodified ligation product. This micelle-based methodology facilitates the generation of natural peptides, like Magainin 2, and the derivatization of the protein Ubiquitin. Formation of mixed micelles from lipid-modified reactants shows promise for accelerating chemical reactions in a traceless manner.
Highlights
Biology utilizes multiple strategies, including sequestration in lipid vesicles, to raise the rate and specificity of chemical reactions through increases in effective molarity of reactants
Given that templated protein synthesis is a principal tenet of the central dogma of molecular biology, it would be of particular interest to understand if lipid moiety mediated self-assembly of mixed micelles[15] can drive the selective formation of discreet polypeptides
We focused on applying lipid modification to accelerate oligopeptide coupling, through native chemical ligation (NCL)[16]
Summary
Biology utilizes multiple strategies, including sequestration in lipid vesicles, to raise the rate and specificity of chemical reactions through increases in effective molarity of reactants. If successful, mixed micelle assistance could provide a straightforward mechanism to accelerate sluggish chemical reactions and could be potentially be a useful synthetic method if mechanisms existed to make the process traceless through removal of lipid auxiliary groups. To address these issues, we focused on applying lipid modification to accelerate oligopeptide coupling, through native chemical ligation (NCL)[16]. Our studies suggest that micelle-mixing assembly may be a broadly applicable method for the acceleration of chemical reactions
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