We reported recently that certain β(3) -peptides self-assemble in aqueous solution into discrete bundles of unique structure and defined stoichiometry. The first β-peptide bundle reported was the octameric Zwit-1F, whose fold is characterized by a well-packed, leucine-rich core and a salt-bridge-rich surface. Close inspection of the Zwit-1F structure revealed four nonideal interhelical salt-bridge interactions whose heavy atom-heavy atom distances were longer than found in natural proteins of known structure. Here we demonstrate that the thermodynamic stability of a β-peptide bundle can be enhanced by optimizing the length of these four interhelical salt bridges. Combined with previous work on the role of internal packing residues, these results provide another critical step in the "bottom-up" formation of β-peptide assemblies with defined sizes, reproducible structures, and sophisticated function.
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