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Design of Cyclic Peptides Featuring Proline Predominantly in the cis Conformation under Physiological Conditions
Author(s) -
Malešević Miroslav,
Schumann Michael,
Jahreis Günther,
Fischer Gunter,
Lücke Christian
Publication year - 2012
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201200366
Subject(s) - chemistry , polyproline helix , stereochemistry , residue (chemistry) , cyclic peptide , conformational isomerism , serine , dihedral angle , proline , alanine , isomerase , tyrosine , peptide , amino acid , prolyl isomerase , molecule , biochemistry , organic chemistry , hydrogen bond , pin1 , enzyme , gene
Turns are secondary‐structure elements that are omnipresent in natively folded polypeptide chains. A large variety of four‐residue β‐turns exist, which differ mainly in the backbone dihedral angle values of the two central residues i +1 and i +2. The βVI‐type turns are of particular biological interest because the i +2 residue is always a proline in the cis conformation and might thus serve as target of peptidyl prolyl cis / trans isomerases (PPIases). We have designed cyclic hexapeptides containing two proline residues that predominantly adopt the cis conformation in aqueous solution. NMR data and MD calculations indicated that the cyclic peptide sequences c‐(‐ D Xaa‐Ser‐Pro‐ D Xaa‐Lys‐Pro‐) result in highly symmetric backbone structures when both prolines are in the cis conformation and the D ‐amino acids are either alanine or phenylalanine residues. Replacement of the serine residue either by phosphoserine or by tyrosine compromises this symmetry, but further increases the cis conformation content of both prolines. As a result, we obtained a cyclic hexapeptide that exists almost exclusively as the cis ‐Pro/ cis ‐Pro conformer but shows no cis / trans interconversion even in the presence of the PPIase Pin1, apparently due to an energetically quite favorable but highly restricted conformational space.