On the Cis to Trans Isomerization of Prolyl–Peptide Bonds under Tension

The cis peptide bond is a characteristic feature of turns
in protein
structures and can play the role of a hinge in protein folding. Such
cis conformations are most commonly found at peptide bonds immediately
preceding proline residues, as the cis and trans states for such bonds
are close in energy. However, isomerization over the high rotational
barrier is slow. In this study, we investigate how mechanical force
accelerates the cis to trans isomerization of the prolyl–peptide
bond in a stretched backbone. We employ hybrid quantum mechanical/molecular
mechanical force-clamp molecular dynamics simulations in order to
describe the electronic effects involved. Under tension, the bond
order of the prolyl–peptide bond decreases from a partially
double toward a single bond, involving a reduction in the electronic
conjugation around the peptide bond. The conformational change from
cis to extended trans takes place within a few femtoseconds through
a nonplanar state of the nitrogen of the peptide moiety in the transition
state region, whereupon the partial double-bond character and planarity
of the peptide bond in the final trans state is restored. Our findings
give insight into how prolyl–peptide bonds might act as force-modulated
mechanical timers or switches in the refolding of proteins.