Conformational Analysis of a Cyclic RGD Peptide Containing a ψ[CH₂-NH] Bond: A Positional Shift in Backbone Structure Caused by a Single Dipeptide Mimetic

The pseudopentapeptide cyclo(-Arg¹-Gly²-Asp³-D-Phe⁴ψ[CH₂-NH] Val⁵-) (1) was synthesized by a combination of solution and solid-phase methods. The reduced peptide bond was incorporated as a dipeptide building block, a versatile synthetic alternative that avoids the reduction of imine intermediates. NMR spectroscopy was used to investigate the structure of the peptide. Interproton distances from a NOESY spectrum served as restraints in a molecular dynamics simulation. Though the peptide exhibits a typical βII',γ conformation with the D-Phe in the i + 1 position of a γ turn, this solution conformation is different from that of the parent peptide cyclo(-Arg¹-Gly²-Asp³-D-Phe⁴- Val⁵-) with the D-Phe in the i + 1 position of βII'. The influence of the reduced peptide bond is examined by computational methods. The ψ[CH₂-NH] bond proved to be a strong hydrogen bond donor and thus rigidifies the peptide backbone.