Acetyl-L-alanine methyl ester

The dissociation kinetics of protonated n-acetyl-L-alanine methyl ester dimer (AcAlaME(d)), imidazole dimer, and their cross dimer were measured using blackbody infrared radiative dissociation (BIRD). Master equation modeling of these data was used to extract threshold dissociation energies (E(o)) for the dimers. Values of 1.18 +/- 0.06, 1.11 +/- 0.04, and 1.12 +/- 0.08 eV were obtained for AcAlaME(d), imidazole dimer, and the cross dimer, respectively. Assuming that the reverse activation barrier for dissociation of the ion-molecule complex is negligible, the value of E(o) can be compared to the dissociation enthalpy (DeltaH(d) degrees ) from HPMS data. The E(o) values obtained for the imidazole dimer and the cross dimer are in agreement with HPMS values; the value for AcAlaME(d) is somewhat lower. Radiative rate constants used in the master equation modeling were determined using transition dipole moments calculated at the semiempirical (AM1) level for all dimers and compared to ab initio (RHF/3-21G*) calculations where possible. To reproduce the experimentally measured dissociation rates using master equation modeling, it was necessary to multiply semiempirical transition dipole moments by a factor between 2 and 3. Values for transition dipole moments from the ab initio calculations could be used for two of the dimers but appear to be too low for AcAlaME(d). These results demonstrate that BIRD, in combination with master equation modeling, can be used to determine threshold dissociation energies for intermediate size ions that are in neither the truncated Boltzmann nor the rapid energy exchange limit.

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.

In this paper we report an experimental conformational analysis of the depsipeptide model compounds acetyl-L-alanine methyl ester, acetyl-L-lactic acid N-methylamide, and acetyl-L-alanyl-L-lactic acid N-methylamide and of the sequential polydepsipeptide poly(L-alanyl-L-lactic acid). The model depsipeptides were examined in dilute organic solutions by infrared and nuclear magnetic resonance spectroscopy. Neither acetyl-L-alanine methyl ester nor acetyl-L-lactic acid N-methylamide assumes an intramolecularly hydrogen-bonded conformation. Acetyl-L-alanyl-L-lactic acid N-methylamide, on the other hand, in dilute chloroform or dilute carbon tetrachloride solutions, strongly favors a conformation with an intramolecular hydrogen bond between the N-H hydrogen atom of its N-methylamide group and the carbonyl oxygen atom of its acetyl group. Comparison of theoretical and experimental circular dichroism suggests that poly(L-alanyl-L-lactic acid) is partially ordered in chloroform solution with approximately 50% of its repeat units in the R10 helix, an ordered conformation found by our previous theoretical analysis to have a low intramolecular conformational energy.