Stereochemistry Rules: A Single Stereocenter Changes the Conformation of a Cyclic Tetrapeptide

Two novel cyclo­(Boc-Cys-Pro-Leu-Cys-OMe)
peptides 1 and 2 containing the enantiomeric
amino acids d-Leu and l-Leu, respectively, were
synthesized to investigate
the effect of chiral centers on peptide conformations. By combining
a variety of experimental techniques (X-ray crystallography, 2D NMR
spectroscopy, temperature-dependent 1H NMR and IR spectroscopy,
and UV-CD spectroscopy) with replica exchange molecular dynamics (REMD)
techniques and quantum mechanics/molecular dynamics (QM/MM) calculations,
we establish that the stereochemistry of just one residue can noticeably
influence the properties of the whole peptide and rationalize the
origins of this effect, with potential implications for the rational
design of peptides of chemical and biological relevance.