Web Release Date: December 1,
Engineering Cyclic Tetrapeptides Containing Chimeric Amino Acids as Preferred Reverse-Turn Scaffolds
and
Center for Computational Biology and Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, Missouri 63110
Received July 22, 2005
Abstract:
Four residues making almost a complete 180
turn in the direction of the peptide chain define a reverse
turn, a common motif and recognition site in proteins. Cyclization between residues i and i + 3 and
incorporation of heterochiral dipeptides (such as D-Pro-L-Pro) in the i + 1 and i + 2 positions are used to
constrain a peptide to a reverse-turn conformation. A combined approach, cyclic tetrapeptides (CTPs) based
on heterochiral dipeptides of chimeric amino acids, is evaluated as minimalist scaffolds for reverse-turn
conformations. Cyclo-(D-Pro-L-Pro-D-Pro-L-Pro) has been studied with density functional theory (DFT)
calculations and molecular dynamics simulations. The all-trans amide conformer was the most stable in
vacuo, while the cis-trans-cis-trans (ctct) or trans-cis-trans-cis (tctc) amide conformer was more favored in
water due to its large dipole moment. Different conformations could be selectively stabilized by different
substitutions on the proline rings. Due to the small 12-membered ring and exocyclic constraints,
conformational interconversions could only occur at high temperature. The presence of seven hydrogens on
each ring that could be functionalized offers an overwhelming diversity to design molecules to probe receptors.
The spatial relationships of C
-C
vectors of reverse turns in proteins were subjected to principal component
analysis for determination of the relative orientation of the C-C vectors. Most reverse-turn structures
could be mimicked effectively with a subset of CTP scaffolds with an root-mean-square displacement (RMSD)
of approximately 0.5 Å. Structural diversity of CTP scaffolds could be enhanced by the incorporation of
proline analogues, such as azaproline (azPro) or pipecolic (Pip), azapipecolic (azPip), nipecotic (Nip), and
isonipecotic (Inp) acids.
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