Extended form of a retro-inverso peptide stabilized by ?-sheet unidirectional H-bonds: Crystallographic and NMR evidence

Abstract

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. 1H‐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 CO · · · HN H‐bonds per residue. © 2001 John Wiley & Sons, Inc. Biopolymers (Pept Sci) 60: 322–332, 2001

The partial retro–inverso modification: A road traveled together

“…24 In this ␤-sheet aggregated structure the two NHs in the gAla and the two COs in the mAla residues are simultaneously in the parallel orientation as predicted by DauberOsguthorpe. 25 Molecular dynamic simulation of the amino acid surrogate residues identified energy barriers between the helical and extended conformations that can be easily overcome by the formation of the two hydrogen bonds per residue in the parallel ␤-sheet aggregate observed in the crystal structure.…”

Synthesis of the Metabolites of 4-(2-Methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide (KRP-197/ONO-8025)

“…N-(1-Aminoethyl)benzamide hydrochloride 11, prepared according to Carotti's method, 5) was transformed to 12 on treatment with chloroacethyl chloride followed by cyclization and protection by the Boc group in 30% yield (3 steps). The ring oxidation re- Ichiro action of 12 was achieved by using bromination with N-bromosuccinimide (NBS) followed by pyridinium dichromate (PDC) treatment to give imidazolidinone 13 in 50% yield.…”

Oxalyl retro-peptide gelators. Synthesis, gelation properties and stereochemical effects

“…Computer simulations of some malonamide retro-peptides have shown that the extended conformations are less stable than the helical ones [48–49]. Nevertheless, the crystal structure of the retro–inverso peptide Bz–S–gAla–R–mAla–NHPh revealed it’s unidirectional self-assembly by intermolecular β-sheet type of hydrogen bonding so that malonamide retro-peptides could be considered as potential candidates for development of new gelator molecules [50]. The oxalamide based retro-peptides are relatively rare and much less studied than the more flexible malonamide retro-peptides [51–54].…”