Protonation of the side group in beta- and gamma-aminated proline analogues: effects on the conformational...

This work shows the influence of the side-chain protonation on the conformational properties, relative stabilities, and peptide bond isomerization of four aminoproline isomers. Thus, this research has been useful to define the rules that allow control the conformation of aminoproline with the pH. Comparison of the results obtained using density functional theory calculations for the N-acetyl-N'-methylamide derivatives of the protonated isomers, which differ in the beta- or gamma-position of the substituent and its cis or trans relative disposition, with those reported for the corresponding neutral analogues (J. Phys. Chem. B 2008, 112, 14045) has allowed us to reach the following conclusions: (i) protonation of the amino group produces a reduction of the backbone conformational flexibility and a destabilization of the cis configuration of the amide bond involving the pyrrolidine nitrogen; (ii) the planarity of the peptide bond is broken in some cases to form strong side chain...backbone interactions, which induce a very significant pyramidilization at the amide nitrogen atom; (iii) as was also detected for the neutral analogues, the formation of side chain...backbone intraresidue interactions favor the cis disposition of the substituent; and (iv) protonation of the amino side group increases the energy gaps that separate the different investigated isomers resulting in an enhancement of the destabilization of the dipeptides with the substituent attached in a trans position.