Conformational preferences and cis-trans isomerization of L-lactic acid residue

The conformational study on N-acetyl- N'-methylamide of l-lactic acid (Ac-Lac-NHMe, the Lac dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore its backbone conformational preferences and cis-trans isomerization for the depsipeptide with an ester bond in the gas phase and in solution. In the gas phase and in chloroform, the conformation tB with a trans depsipeptide bond is most preferred for the Lac dipeptide, whose backbone torsion angles are phi approximately -150 degrees and psi approximately -5 degrees , juxtaposed to those of the 3 10-helical structure. The larger shift in phi is brought to reduce the repulsion between the two carbonyl carbons of the acetyl and NHMe groups. However, the polyproline II-like tF conformation becomes more populated and the relative stability of conformation tB decreases significantly as the solvent polarity increases. This may be ascribed to weakening a C(5) hydrogen bond between the depsipeptidyl oxygen and the carboxyl amide hydrogen that plays a role in stabilizing the conformation tB in the gas phase and in chloroform. The cis populations about the depsipeptide bond are nearly negligible in the gas phase and in solution. The rotational barriers to the cis-trans isomerization of the depsipeptide bond for the Lac dipeptide are calculated to be about 11 kcal/mol, which is about half of those for the Ala dipeptide, although they increase somewhat with the increase of solvent polarity. The cis-trans isomerization of the depsipeptide bond proceeds through either clockwise or anticlockwise rotations with torsion angles of about +90 degrees or -90 degrees , respectively, in the gas phase and in solution, whereas it has been known that the isomerization proceeds through only the clockwise rotation for alanyl and prolyl peptide bonds. The pertinent distances between the depsipeptidyl oxygen and the carboxyl amide hydrogen can describe the role of this hydrogen bond in stabilizing the transition state structures in the gas phase and in solution.