Comparative conformational analyses and molecular dynamics studies of glycylglycine methyl ester and glycylglycine N-methylamide

Compared to their amide analogs, peptidic esters have a lower propensity for intramolecular hydrogen bonding, and thus most likely quite different stable geometries. On the other hand, their similarity and facile conversion to peptides has led to their broad use in synthetic and biological applications. This dichotomy creates a need to understand their conformational properties. Here, we study the geometries of glycylglycine methyl ester (GGMe, the simplest dipeptide ester) and its amide counterpart (GGAm) using density functional methods. The optimized conformational states were analysed in gas phase and also using a dielectric continuum aqueous phase model. In addition, molecular dynamics studies were carried out to explore effects of molecular water solvation on structure and conformational flexibility. The two atom change, from amide to ester, results in significantly different conformational profiles and solvation characteristics. In gas phase calculations, the strength of the CO-HN (3/1) intramolecular hydrogen bond in GGAm determines its minimum energy conformation, while GGMe is extended; cis-geometries are more energetic by 6 or 5 kcal mol(-1) for the two molecules, respectively. The addition of a continuum dielectric to model an aqueous phase environment weakens hydrogen bonding such that the intramolecular H-bonds are replaced by geometries with less internal strain and more ideal chemical topologies. As a further consequence of the electrostatic shielding, the relative energies of the cis-geometries are reduced by more than half. Molecular dynamics simulations predict GGAm to be more flexible and more extensively solvated than GGMe. Roughly 40% of the increased solvation is due to the additional hydrogen bond donor NH group of the amide; the rest is due to increased hydrogen bonding to the amide oxygen. These analyses of the solvent dependent structural characteristics of simple peptides and peptide esters provide a basis for understanding and design applications in biological recognition, drug design, and synthetic chemistry.