Assessment of Energy Effects Determining <i>cis</i> - <i>trans</i> 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 <i>cis-trans</i> equilibria of short peptides: capped Ac-Z-NHMe, Ac-X-Z-NHMe, and <i>zwitterionic</i> 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 <i>→</i> Pro substitution stabilizes the Ac/X-Z <i>cis</i> 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 <i>cis-trans</i> 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 <i>trans</i> and <i>cis</i> isomer of the Ala- and Pro-containing capped peptides, respectively, suggesting thus that solvation plays a key role in the Pro <i>cis</i> effect observed in these systems in agreement with former proposals.