Conformational preferences of β-sheet structures in cyclopropane-containing γ-peptides

Abstract

The conformational preferences of β-sheets in oligo-γ-peptides composed of 2-(aminomethyl)cyclopropanecarboxylic acid (γAmc₃) with a cyclopropane constraint on the C^α–C^β bond were studied using density functional theory (DFT) methods in the gas phase and in solution (chloroform and water). Parallel β-sheets were preferred over the corresponding antiparallel β-sheets in the gas phase. The propensity to form parallel β-sheets increased as the length of the peptide sequence was increased. Parallel β-sheets had larger inter-strand N–H⋯O H-bond energies, whereas antiparallel β-sheets had slightly favored C–H⋯O energies and smaller deformation energies. Thus, the greater stability of parallel β-sheets can be ascribed to the formation of stronger N–H⋯O H-bonds. Antiparallel β-sheets exhibited more favored solvation free energies than did the corresponding parallel β-sheets. Although parallel β-sheets were more stable than antiparallel β-sheets in chloroform, parallel and antiparallel β-sheets exhibited nearly similar stabilities for the tetrapeptide and hexapeptide in water. The greater importance of desolvation in parallel β-sheets compared with antiparallel β-sheets may be partially attributable to the formation of stronger inter-strand N–H⋯O H-bonds in parallel β-sheets. DFT calculations supported the formation of parallel β-sheets for the tetrapeptide and hexapeptide in chloroform, consistent with experimental data for γAmc₃-containing peptides that form parallel β-sheets in CDCl₃. The conformational preferences of β-sheets determined here will provide useful information for understanding the conformational preferences of other oligo-γ-peptides with specific functions.