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-NH2 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-NH2.