A Conformationally Stable Acyclic β-Hairpin Scaffold Tolerating the Incorporation of Poorly β-Sheet-Prone Amino Acids.

The β-hairpin is a structural element of native proteins, but it is also a useful artificial scaffold for finding lead compounds to convert into peptidomimetics or non-peptide structures for drug discovery. Since linear peptides are synthetically more easily accessible than cyclic ones, but are structurally less well-defined, we propose XWXWXpPXK(/R)X(R) as an acyclic but still rigid β-hairpin scaffold that is robust enough to accommodate different types of side chains, regardless of the secondary-structure propensity of the X residues. The high conformational stability of the scaffold results from tight contacts between cross-strand cationic and aromatic side chains, combined with the strong tendency of the d-Pro-l-Pro dipeptide to induce a type II' β-turn. To demonstrate the robustness of the scaffold, we elucidated the NMR structures and performed molecular dynamics (MD) simulations of a series of peptides displaying mainly non-β-branched, poorly β-sheet-prone residues at the X positions. Both the NMR and MD data confirm that our acyclic β-hairpin scaffold is highly versatile as regards the amino-acid composition of the β-sheet face opposite to the cationic-aromatic one.