Exploring the ability of cyclic peptides to target SAM domains: a computational and experimental study

SAM domains are protein interaction modules with a helical fold. SAM-SAM interactions often adopt the Mid-Loop (ML)/End-Helix (EH) model in which the C-terminal helix and adjacent loops of one SAM unit (EH site) bind the central regions of another SAM domain (ML site). Herein, an original strategy to attack SAM-SAM associations is reported. It relies on the design of cyclic peptides targeting a region of the SAM domain positioned at the bottom side of the EH interface, that is thought to be important for the rise of a SAM-SAM complex. We preliminarily tested this strategy by using as model system heterotypic SAM-SAM interactions involving EphA2 receptor and implementing a multidisciplinary plan made up of computational docking studies, experimental interaction assays (by NMR and SPR techniques) and conformational analysis (by NMR and CD). This work further highlights how only a specific balance between flexibility and rigidity may be needed to generate modulators of SAM-SAM interactions.