Diversity of Secondary Structure in Catalytic Peptides with β‑Turn-Biased Sequences

X-ray
crystallography has been applied to the structural analysis
of a series of tetrapeptides that were previously assessed for catalytic
activity in an atroposelective bromination reaction. Common to the
series is a central Pro-Xaa sequence, where Pro is either l- or d-proline, which was chosen to favor nucleation of
canonical β-turn secondary structures. Crystallographic analysis
of 35 different peptide sequences revealed a range of conformational
states. The observed differences appear not only in cases where the
Pro-Xaa loop-region is altered, but also when seemingly subtle alterations
to the flanking residues are introduced. In many instances, distinct
conformers of the same sequence were observed, either as symmetry-independent
molecules within the same unit cell or as polymorphs. Computational
studies using DFT provided additional insight into the analysis of
solid-state structural features. Select X-ray crystal structures were
compared to the corresponding solution structures derived from measured
proton chemical shifts, 3J-values, and 1H–1H-NOESY contacts. These findings imply
that the conformational space available to simple peptide-based catalysts
is more diverse than precedent might suggest. The direct observation
of multiple ground state conformations for peptides of this family,
as well as the dynamic processes associated with conformational equilibria,
underscore not only the challenge of designing peptide-based catalysts,
but also the difficulty in predicting their accessible transition
states. These findings implicate the advantages of low-barrier interconversions
between conformations of peptide-based catalysts for multistep, enantioselective
reactions.