Conformational heterogeneity of a turn mimetic pseudo-peptide: comparison of crystal state, solution and theoretically derived structures

Abstract

Crystal structure analysis of the pseudo-peptide (tert-Butyl N-{2-[ N-(N, N'-dicyclohexyl-ureidocarbonylethyl)carbamoyl]-prop-2-yl}carbamate) exhibited presence of a 13-membered intramolecular hydrogen bonded structure involving Boc C═O and Urea NH group to form an α-turn mimic [Acta Crystallogr. C 56 (2000) 1120]. However, NMR studies of this compound in CDCl₃ using DMSO solvent titration of amide NH groups have revealed that the pseudo-peptide lacks of unique conformational state in solution. We have therefore carried out ab initio quantum mechanical calculations at up to B3LYP/6-31G** using density function theory level to characterise relative stabilities of different possible conformations with distinctive hydrogen bonding patterns. Computational studies also reveal that a 13-atom hydrogen bonded turn, identical to the crystal state conformation and analogous to the α-turn (in proteins) is energetically most stable. The structures with 7-atom hydrogen bonded turn (γ-turn) and with bifurcated hydrogen bonds are, however, seen to have energies quite comparable to that of the α-turn mimetic. This indicates possibility of existence of multiple conformational states, corresponding to various turn structures (viz. α-turn mimetic, γ-turn, etc.) which may interconvert in NMR time scale.