Taste for Chiral Guests: Investigating the Stereoselective
Binding of Peptides to β‑Cyclodextrins
- Publication date
- Publisher
Abstract
Obtaining compounds of diastereomeric
purity is extremely important
in the field of biological and pharmaceutical industry, where amino
acids and peptides are widely employed. In this work, we theoretically
investigate the possibility of chiral separation of peptides by β-cyclodextrins
(β-CDs), providing a description of the associated interaction
mechanisms by means of molecular dynamics (MD) simulations. The formation
of host/guest complexes by including a model peptide in the macrocycle
cavity is analyzed and discussed. We consider the terminally blocked
phenylalanine dipeptide (Ace-Phe-Nme), in the l- and d-configurations, to be involved in the host/guest recognition
process. The CD–peptide free energies of binding for the two
enantiomers are evaluated through a combined approach that assumes:
(1) extracting a set of independent molecular structures from the
MD simulation, (2) evaluating the interaction energies for the host/guest
complexes by hybrid quantum mechanics/molecular mechanics (QM/MM)
calculations carried out on each structure, for which we also compute,
(3) the solvation energies through the Poisson–Boltzmann surface
area method. We find that chiral discrimination by the CD macrocycle
is of the order of 1 kcal/mol, which is comparable to experimental
data for similar systems. According to our results, the Ace-(d)Phe-Nme isomer leads to a more stable complex with a β-CD
compared to the Ace-(l)Phe-Nme isomer. Nevertheless, we show
that the chiral selectivity of β-CDs may strongly depend on
the secondary structure of larger peptides. Although the free energy
differences are relatively small, the predicted selectivities can
be rationalized in terms of host/guest hydrogen bonds and hydration
effects. Indeed, the two enantiomers display different interaction
modes with the cyclodextrin macrocavity and different mobility within
the cavity. This finding suggests a new interpretation for the interactions
that play a key role in chiral recognition, which may be exploited
to design more efficient and selective chiral separations of peptides