Assessment of Energy Effects Determining cis-trans Proline Isomerization in Dipeptides.

Herein, we present the results of molecular dynamics, potential of mean force (PMF) and quantum mechanical (QM) calculations aimed to investigate the equilibria of short peptides: capped Ac-Z-NHMe, Ac-X-Z-NHMe, and Leu-Z with X = Gln, Leu, Tyr and Z = Pro, Ala. Both PMF free energies and average QM energies in aqueous solution consistently predict that the Ala Pro substitution stabilizes the Ac/X-Z isomer in all the model compounds. Using the interacting quantum atoms method, we decomposed the average QM energies into physical components and performed a comparative analysis between the Pro-containing peptides and their Ala-substituted counterparts. The results point out that isomerization is not controlled by a single steric or electronic contribution and unveil a mixture of electrostatic, steric and hyperconjugative effects that is modulated by the dipeptide sequence. It is also shown that solute-solvent interactions stabilize systematically the and isomer of the Ala- and Pro-containing capped peptides, respectively, suggesting thus that solvation plays a key role in the Pro effect observed in these systems in agreement with former proposals.