MODEL FOR THE INTERACTION OF AMPHIPHILIC HELICES WITH TROPONIN-C AND CALMODULIN

Crystals of troponin are stabilized by an intermolecular interaction that involves the packing of helix A from the N‐terminal domain of one molecule onto the exposed hydrophobic cleft of the C‐terminal domain of a symmetry related molecules. Analysis of this molecular recognition interaction in troponin C suggests a possible mode for the binding of amphiphilic helical molecules to troponin C and to calmodulin. From the template provided by this troponin C packing, it has been possible to build a model of the contact region of mastoporan as it might be bound to the two Ca2+ binding proteins. A possible binding mode of melittin to calmodulin is also proposed. Although some of the characteristics of binding are similar for the two amphiphilic peptides, the increased length of melittin requires a significant bend in the calmodulin central helix similar to that suggested recently for the myosin light chain kinase calmodulin binding peptide (Persechini and Kretsinger: Journal of Cardiovascular Pharmacology 12:501–512, 1988). Not only are the hydrophobic interactions important in this model, but there are several favorable electrostatic interactions that are predicted as a result of the molecular modeling. The regions of troponin‐C and calmodulin to which amphiphilic helices bind are similar to the regions to which the neuroleptic drugs such as trifluoperazine have been predicted to bind (Strynadka and James: Proteins 3:1–17, 1988). Copyright © 1990 Wiley‐Liss, Inc.