Computational studies on the backbone‐dependent side‐chain orientation induced by the ( S,S )‐CXC motif

Disulfide cyclization is a well‐known procedure to impose conformational restriction to peptides undergoing backbone flexibility. Rigid conformations are induced only for small rings with a specific combination of amino acids. In this work, we present a computational search of the backbone and backbone‐dependent side‐chain orientation of two series of linear and cyclic peptide analogs. The ‐C[XY]C‐ scaffold (where X,Y is arginine, aspartic acid or alanine residue) in its open and ( S,S ) cyclic form was used for the design of the studied analogs. Thirty‐six compounds, resulting from the extension with one residue at either the N ‐ or the C ‐terminus were studied with classical MD. The local backbone conformation and the relative orientation of the X and Y side chains induced by either cyclization and/or the presence of the charged residues are discussed. From the present study it is concluded that cyclization has a great impact on the synplanar orientation of the X and Y side chains in the ( S,S )Ac‐XCYC‐NH 2 series of compounds while charge–charge interaction has only a weak synergic effect. On the contrary, the antiplanar orientation is favored in the case of (S,S)Ac‐CXCY‐NH 2 . Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.