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

## TL;DR

This paper investigates how replacing alanine with proline affects the cis-trans isomerization in dipeptides using computational methods.

## Contribution

The study reveals that cis-trans isomerization in dipeptides is influenced by a combination of electrostatic, steric, and hyperconjugative effects.

## Key findings

- Ala → Pro substitution stabilizes the cis isomer in model dipeptides.
- Solvation effects stabilize trans isomers in alanine and cis isomers in proline-containing peptides.
- Multiple physical effects modulate isomerization, not a single factor.

## Abstract

Herein, we present the results of molecular dynamics,
potential
of mean force (PMF) and quantum mechanical (QM) calculations aimed
to investigate the cis–trans equilibria of
short peptides: capped Ac-Z-NHMe, Ac-X-Z-NHMe, and zwitterionic 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 cis 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 cis–trans 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 trans and cis isomer of the Ala- and Pro-containing
capped peptides, respectively, suggesting thus that solvation plays
a key role in the Pro cis effect observed in these
systems in agreement with former proposals.