Conformational properties of the residues connected by ester and methylated amide bonds: theoretical and solid state conformational studies

Peptides produced by bacteria and fungi often contain an ester bond in the main chain. Some of them have both an ester and methylated amide bond at the same residue. A broad spectrum of biological activities makes these depsipeptides potential drug precursors. To investigate the conformational properties of such modified residues, a systematic theoretical analysis was performed on N ‐acetyl‐ L ‐alanine N ′‐methylamide (Ac‐Ala‐NHMe) and the analogues with the ester bond on the C ‐terminus (Ac‐Ala‐OMe), N ‐terminus (Ac‐[psi](COO)‐Ala‐NHMe) as well as the analogues methylated on the N ‐terminus (Ac‐(Me)Ala‐OMe) and C ‐terminus (Ac‐[psi](COO)‐Ala‐NMe 2 ). The ϕ, ψ potential energy surfaces and the conformers localised were calculated at the B3LYP/6‐311++G(d,p) level of theory both in vacuo and with inclusion of the solvent (chloroform, water) effect (SCRF method). The solid state conformations of the studied residues drawn from The Cambridge Structural Database have been also analysed. The residues with a C ‐terminal ester bond prefer the conformations β, C5, and α R , whereas those with N ‐terminal ester bond prefer the conformations β, α R , and the unique conformation α′ (ϕ, ψ = −146°, −12°). The residues with N ‐terminal methylated amide and a C ‐terminal ester bond prefer the conformations β, β2, and interestingly, the conformation α L . The residues with a C ‐terminal methylated amide and an N ‐terminal ester bond adopt primarily the conformation β. The description of the selective structural modifications, such as those above, is a step towards understanding the structure‐activity relationship of the depsipeptides, limited by the structural complexity of these compounds. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.