De novo design of peptides targeted to the EF hands of calmodulin

This report describes the use of the concept of inversion of hyrdropathy pa tterns to the de novo design of peptides targeted to a predetermined site o n a protein. Eight- and la-residue peptides were constructed with the EF ha nds or Ca2+-coordinating sites of calmodulin as their anticipated points of interaction. These peptides, but not unrelated peptides nor those with the same amino acid composition but a scrambled sequence, interacted with the two carboxyl-terminal Ca2+-binding sites of calmodulin as well as the EF ha nds of troponin C. The interactions resulted in a conformational change whe reby the 8-mer peptide-calmodulin complex could activate phosphodiesterase in the absence of Ca2+. In contrast, the la-mer peptide-calmodulin complex did not activate phosphodiesterase but rather inhibited activation by Ca2+. This inhibition could be overcome by high levels of Ca2+. Thus, it would a ppear that the afore-mentioned concept can be used to make peptide agonists and antagonists that are targeted to predetermined sites on proteins such as calmodulin.