Stereochemically constrained peptides. Theoretical and experimental studies on the conformations of peptides containing 1-aminocyclohexanecarboxylic acid

Abstract

Conformational energy calculations on the model system N-acetyl- 1 -aminocyclohexanecarboxylic acid N′methylamide (Ac-Acc⁶-NHMe), using an average geometry derived from 13 crystallographic observations, establish that the Acc⁶ residue is constrained to adopt conformations in the 3₁₀/α-helical regions of ∅ ψ space (∅ = ± 50 ± 20° , ψ = ± 50 ± 20°). In contrast, the α, α -dialkylated residue with linear hydrocarbon side chains, α, α-di-n-propylglycine favors fully extended backbone structures (∅ ≈ ψ ≈ 180°). The crystal structures of two model peptides, Boc-(Acc⁶)3-OMe (type III β-turn at -Acc⁶(1)-Acc⁶(2)-) and Boc-Pro-Acc⁶-Ala-OMe (type II β-turn at -Pro-Acc⁶-), establish that Acc⁶ residues can occupy either position of type III β-turns and the i + 2 position of type II β -turns. The stereochemical rigidity of these peptides is demonstrated in solution by NMR studies, which establish the presence of one intramolecular hydrogen bond in each peptide in CDCl₃, and (CD₃)₂SO. Nuclear Overhauser effects permit characterization of the β-turn conformations in solution and establish their similarity to the solid-state structures. The implications for the use of Acc⁶ residues in conformational design are considered.