(33a) Enhanced Liquid-Phase Synthesis and Interfacial Self-Assembly of Amphipathic Polypeptides

Synthesizing useful, self-assembling, periodically-sequenced amphipathic polypeptides is challenging due to the polydispersity index increase of progressively larger molecular weight polymer systems. To offset this, we designed synthetic amino acid dimers that polymerize into an amphipathic chain with alternating hydrophilic/hydrophobic side groups.  This periodicity is typical of peptide sequences prone to self-assembly into beta-sheets. In this way, we influence polydispersity in the growing polypeptide chains: controlling the kinetics of growth through transport-limited chain elongation. Our experiments show that in the absence of a micellular interface, standard bulk-phase condensation polymerization occurs. The amphipathic character of the peptide chain increases with increasing molecular weight, resulting in a polypeptide that partitions into surfactant micelles as a function of molecular weight. This type of kinetically-limited growth serves to narrow the polydispersity of our periodically-sequenced polypeptide. We quantify the dynamics of chain elongation and interfacial assembly using multi-angle light scattering and define the evolving sheet-like secondary structure using circular dichroism for various peptides of differing amino acid pairs. Our results show that the peptides grown in the presence of micelles show significantly enhanced self-assembly and a narrowed polydispersity index. These self-assemblies are characterized further as Langmuir-Blodgett films, and imaged using Brewster angle microscopy.  From these, we conclude that the transport-limited chain elongation polymerization method shows great promise in the manufacture of low-cost, interfacially-assembling polypeptides.