β-Peptide Bundles with Fluorous Cores

We reported recently that certain β-peptides self-assemble spontaneously into cooperatively folded bundles whose kinetic and thermodynamic metrics mirror those of natural helix bundle proteins. The structures of four such β-peptide bundles are known in atomic detail. These structures reveal a solvent-sequestered, hydrophobic core stabilized by a unique arrangement of leucine side chains and backbone methylene groups. Here we report that this hydrophobic core can be re-engineered to contain a fluorous subdomain while maintaining the characteristic β-peptide bundle fold. Like α-helical bundles possessing fluorous cores, fluorous β-peptide bundles are stabilized relative to hydrocarbon analogues and undergo cold denaturation. β-Peptide bundles with fluorous cores represent the essential first step in the synthesis of orthogonal protein assemblies that can sequester selectively in an interstitial membrane environment.