Presence of an amphipathic helical segment and its relationship to biological potency of calcitonin analogs.

The conformational properties of a number of calcitonin analogs were studied by circular dichroism. The ability of dimyristoylphosphatidylglycerol, lysophosphatidylcholine or sodium dodecyl sulfate to induce the formation of more highly ordered structures in these peptides was also assessed by circular dichroism. In all cases sodium dodecyl sulfate induced the largest change in the circular dichroism spectra of the peptides. Salmon calcitonin and its analogs were slightly more helical in the presence of the anionic phospholipid than in the presence of the zwitterionic detergent lysophosphatidylcholine while the reverse is true for human calcitonin and its analogs. Some of the calcitonin analogs convert turbid suspensions of phosphatidylglycerol to a clear solution from which the phospholipid is no longer readily sedimentable by centrifugation. Several of the physical properties of these peptides could be correlated with their biological activity. Generally peptides which showed no hypocalcemic activity had the least negative mean residue ellipticities at 222 nm. Only biologically active analogs were able quantitatively to solubilize dimyristoyl-phosphatidylglycerol and in this solubilized form the peptides have a higher helical content. More active derivatives exhibit larger increases in helix content in the presence of this phospholipid. Inactive analogs had the least negative mean residue ellipticities at 222 nm in the presence of lysophosphatidylcholine or sodium dodecyl sulfate. Thus, the ability of a calcitonin analog to form structures of higher helical content in the presence of amphiphiles is a requirement for the analog to exhibit high potency in assays of biological activity.