Conformational Studies Using Molecular Mechanics on Model Peptides with 1-Aminocycloalkane 1-Carboxylic Acid Residues

Peptides with conformationally restricted 1-aminocyclopropane-1-carboxylic acid (Acc3) moieties were previously shown to exhibit preference for γ-turn structures in the solution phase and solid phase. We present conformational energy calculations on model compounds containing 1-aminocycloalkane carboxylic acid with 4, 5, and 6-membered rings using molecular mechanics methods. The low-energy models adopt conformations characteristic of a variety of regular structures, such as the α-helix, γ-turn, and polyproline-II-type three- and four-fold helices. The energetically most favored models adopt the γ-turn (2.27 helix) conformation in the model peptide of 1-aminocyclobutane-1-carboxylic acid (Acc4), similar to Acc3 peptides, while they adopt the α-/310-helical conformation (of either handedness) in the corresponding compounds with cyclopentane (Acc5) and cyclohexane (Acc6). The salient features of our investigations are qualitatively consistent with the crystal structures of peptide analogs containing Acc4, Acc5, and Acc6 and the previously reported solution phase and conformational studies on peptides containing Acc5. Our results have implications for the design of γ-turn and α-/310-helical peptidomimetics.