Extended form of a retro–inverso peptide stabilized by β‐sheet unidirectional H‐bonds: Crystallographic and NMR evidence

The crystallographic investigation of the retro–inverso peptide Bz–S–gAla–R–mAla–NHPh reveals an extended backbone conformation where the NH groups of the gem‐diamino alkyl moiety and the CO groups of the malonyl residue face side by side. This extended conformation, presenting all carbonyls on opposite sides of the NH groups, is stabilized by interstrand H‐bonds running in a single direction of the parallel β‐sheets that characterize the crystal packing. These sheets differ from the β‐sheets formed by native amino acids only. 1 H‐NMR nuclear Overhauser effect spectroscopy (NOESY) experiments suggest that a conformation similar to that found in the crystal also prevails in dimethylsulfoxide solution. Previous potential energy calculations of gem‐diamino alkyl (g) and malonyl (m) Ala residues predicted that extended forms were less stable than the helical ones because of strong electrostatic repulsions between the parallel polar groups. Similar arguments were invoked to give more weight to helical forms of the retro‐peptide units in the proposal of packing models of some nylons in their crystalline polar regions. The present findings show that both g and m Ala residues can experience the extended conformation in the β‐sheet aggregation. The energy increase occurring in one strand, due to the parallel orientation of consecutive peptide dipoles, is more than compensated by favorable cooperative interactions among head‐to‐tail aligned peptide dipoles of facing strands, resulting in the formation of two CO · · · HN H‐bonds per residue. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 60: 322–332, 2001