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

Abstract

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 phi, psi 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 beta, C5, and alpha(R), whereas those with N-terminal ester bond prefer the conformations beta, alpha(R), and the unique conformation alpha' (phi, psi = -146 degrees , -12 degrees ). The residues with N-terminal methylated amide and a C-terminal ester bond prefer the conformations beta, beta2, and interestingly, the conformation alpha(L). The residues with a C-terminal methylated amide and an N-terminal ester bond adopt primarily the conformation beta. 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.

The conformational properties of dehydrobutyrine and dehydrovaline: theoretical and solid‐state conformational studies

“…Figure 6 depicts the molecular conformations and arrangements of the Ac‐( Z )‐ΔAbu‐NHMe and Ac‐ΔVal‐NHMe molecules in the solid state. The determined bond distances and valence angles in both studied compounds are similar to those found in other related structures50–55. The torsion ϕ and ψ angles adopted for Ac‐( Z )ΔAbu‐NHMe and Ac‐ΔVal‐NHMe molecules are − 67.4°, − 16.7° and 50.5°, − 139.2°, respectively, together with the opposite values (67.4°, 16.7° and − 50.5°, 139.2°) characteristic for each two molecules related by inversion centres presented in the crystal structures.…”

“…In the hereunto presented solid structure Ac‐ΔVal‐NHMe, the residue adopts the conformations of the torsion angles ϕ, ψ = − 51°, 139° and 51°, − 139°, which correspond to the calculated conformer β and − β. It should be noted that dehydroizoleucine also reveals a similar tendency50, 55, 56. Furthermore, synthesised novel axially chiral dehydroamino acids (4‐alkylcyclohexylidene)glycines, adopt the conformation β57, 58.…”

“…It is confirmed by the conformations in the solid state (Table 3, Figure 5C). The literature data shows that the conformation α50–53 and β54, 55 is adopted in the crystals. In the hereunto presented solid structure Ac‐ΔVal‐NHMe, the residue adopts the conformations of the torsion angles ϕ, ψ = − 51°, 139° and 51°, − 139°, which correspond to the calculated conformer β and − β.…”

The conformational properties of α,β‐dehydroamino acids with a C‐terminal ester group

“…The specific conformational feature of the studied α, β‐dehydroamino acids is the ability to adopt a semi‐extended conformation β2. This conformation is not found for saturated depsipeptides61. The conformation β2 is predicted by theoretical calculations for analogous dehydroamino acid amides but generally it has relatively high energy.…”

Amide-to-Ester Substitution Improves Membrane Permeability of a Cyclic Peptide Without Altering Its Three-Dimensional Structure

“…[7][8][9] However, N-methylation often changes the conformations of peptides because the free energy landscapes of peptides and N-methylated peptides are significantly different. 10 These changes of conformational states can yield increased potency, but more often result in undesired activity loss or selectivity change. [7][8][9]11 Therefore, other strategies that reduce the number of N-H groups but do not affect the original conformations of peptides are desired.…”