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 $(Ac-Acc^6-NHMe)$, using an average geometry derived from 13 crystallographic observations, establish that the $Acc^6$ residue is constrained to adopt conformations in the $3_{10}/\\alpha$-helical regions of \\o \\psi space $(\\o = \\pm 50 \\pm 20^0$ , $\\psi = \\pm 50 \\pm 20^0)$. In contrast, the \\alpha, \\alpha -dialkylated residue with linear hydrocarbon side chains, \\alpha, \\alpha-di-n-propylglycine favors fully extended backbone structures $(\\o \\approx \\psi \\approx = 180^0)$. The crystal structures of two model peptides, Boc-($Acc^6)_3$-OMe (type III \\beta -turn at $-Acc^6(1)-Acc^6(2)-)$ and Boc-Pro-$Acc^6$-Ala-OMe (type II \\beta -turn at -Pro-$Acc^6$-), establish that $Acc^6$ residues can occupy either position of type III \\beta turns and the i + 2 position of type II \\beta -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 $CDCl_3$, and $(CD_3)_2SO$. Nuclear Overhauser effects permit characterization of the \\beta -turn conformations in solution and establish their similarity to the solid-state structures. The implications for the use of $Acc^6$ residues in conformational design are considered.