Understanding the Conformational Properties of Fluorinated Polypeptides: Molecular Modelling of Unguisin A

In this work, we investigate the
conformational properties of unguisin
A, a natural macrocyclic heptapeptide that incorporates a γ-aminobutyric
acid (Gaba), and four of its difluorinated stereoisomers at the Gaba
residue. According to nuclear magnetic resonance (NMR) experiments,
their secondary structure depends dramatically on the stereochemistry
of the fluorinated carbon atoms. However, many molecular details of
the structure and flexibility of these systems remain unknown, so
that a rationale of the conformational changes induced by the fluorine
atoms in the macrocycle is still missing. To fill this gap, we apply
enhanced molecular dynamics (MD) techniques to explore the peptide
conformational space in dimethyl sulfoxide solution followed by 4–8
μs of conventional MD simulations that provide extensive equilibrium
sampling. The simulations, which compare reasonably well with the
NMR-based observations, show that the secondary structure of the macrocycle
is altered substantially upon fluorination, except for the (S,S) diastereomer. It also turns out that the conformations
of the fluorinated peptides are visited during the enhanced MD simulation
of natural unguisin A, suggesting thus that conformations accessible
to the unsubstituted macrocyclic peptide may be selected by fluorination.
Therefore, computational characterization of the macrocyclic peptides
could be helpful in the rational design of stereoselective fluorinated
peptides with fine-tuned conformation and activity.