As shown earlier , interaction with the bilayer significantly restricts the conformational mobility of the cyclic peptides compared to that in water. Regardless of the starting model -flat or bend conformations found in water -binding to the membrane did not induce significant changes in the spatial structure (the average RMSD values of the backbone atoms are ~0.5 Å). Similar to other cyclic AMP peptides analyzed , the most populated membrane-bound mode, the peptides interact with the lipid polar head groups through the Arg residues, while the peptide's hydrophobic motif is oriented toward the solvent (named earlier as mode "UP" or "polar"). Compared to UP-mode, membrane binding through apolar residues (apolar mode) is characterized by a larger contact area and a smaller distance between the peptide center of the mass and the bilayer center.