Design of Cyclic Peptides - Peptide and Protein Design for Biopharmaceutical Applications - page 152

To conclude, the purpose of mentioning these facts is to warn the
reader against believing noncritically all published conformations of
(cyclic) peptides.
4.4 CONCEPTS IN THE RATIONAL DESIGN OF
CYCLIC PEPTIDES
4.4.1 The Influence of Amino Acid Composition
The introduction of special amino acids and the use of building blocks
with varying chiralities can strongly bias the conformation of cyclic
peptides. Since this knowledge contributes evidently to the concepts
applied in rational design, a brief overview of the most prominent
examples is given below.
4.4.1.1 Glycine and proline as building blocks of special impact
Conformational investigations of cyclic peptides by NMR spectro-
scopy show that their structure is strongly influenced by the amino
acids and their chiralities. Glycine, which has no side chain, is usually
foundinflexibleregionsandalsoinproteinswhenothersidechains
sterically interfere (see e.g. the GXXXG motif in helix-helix interac-
tions of proteins) [109,110]. Proline is the only natural proteinogenic
amino acid with a secondary amino group. Hence, glycine and proline
have a strong impact on the conformational preference in cyclic pep-
tides. Glycine is the sterically least hindered amino acid. Therefore, it
easily substitutes L -aswellas D -amino acids and usually occupies the
i þ 1 position in a type II 0 b-turn if the remaining amino acids are in
L -configuration. Proline, on the other hand, is the conformationally
most restrained amino acid and thus induces stronger structural
preferences to the remaining peptide chain.
4.4.1.2 The influence of changes in amino acid chiralities
The incorporation of amino acids with different chiralities offers an
efficient way of actively influencing the side-chain orientation by con-
trolled induction or (re)positioning of turns. Due to steric hindrance