Macrocyclic Design Strategies for Small, Stable Parallel β-Sheet Scaffolds

Pairs of short peptide strands can be induced to adopt an antiparallel beta-sheet secondary structure in aqueous solution via a macrocyclic constraint, as illustrated by many natural and designed peptides. We show that an analogous strategy is successful for creation of small units of parallel beta-sheet secondary structure in aqueous solution. Cyclization in this case requires nonpeptide segments for N-to-N and C-to-C interstrand linkage. Surprisingly, we find that only one of these segments needs to be preorganized.