(43d) Stereoregularity Inhibits Complex Coacervation of Polypeptides

Complex coacervation is a liquid-liquid phase separation phenomenon resulting from the electrostatic complexation of oppositely charged polyelectrolytes.  The resultant fluid phase (coacervate) is a dense, polymer-rich liquid retaining both water and salt.  Coacervates are common in everyday life, present in applications ranging from electronic displays to food and cosmetics.  Coacervates also play a key role in the protein-based underwater adhesives used by sessile marine animals. Emerging experience has shown that these liquid polyelectrolyte complexes can be formed using charged polypeptides. The dense, amino acid-rich coacervate phases formed from polypeptides have tremendous potential as mimics for the crowded intracellular environment where sequence specificity can be used to tailor the available molecular interactions.  Furthermore, the liquid-liquid phase separation of the droplet enables sequestration of encapsulated materials, such as proteins, from the external environment in a manner similar to intracellular organelles. 

In addition to sequence, another very interesting feature available in polypeptide-based systems is the ability to control chirality.  Naturally occurring proteins are composed almost entirely of left-handed, or L-amino acids.  This homochirality is critical for protein folding and the formation of compact tertiary structures.  However, the fluid nature of a coacervate appears to be incompatible with homochiral polypeptides.  Instead, coacervation requires that one or more of the polypeptides have a racemic character. The solid precipitates that form from the electrostatic complexation of oppositely charged, chiral polypeptides (L+L, L+D, D+L, D+D) have an aggregated beta strand structure reminiscent of fibrils.  Long stretches of homopolypeptides have been linked to disorders such as Huntington’s disease.  We are exploring the role of chirality and tacticity on the formation of liquid coacervates as opposed to solid fibrillar precipitates. This work, coupled with investigations on the effect of incorporating different amino acids has the potential to elucidate pathways whereby natural proteins have evolved to utilize diversity of amino acid sequence to favor assembly into a (folded) equilibrium structure over a kinetically trapped fibrillar state.