The use of a metal template was explored as a strategy for controlling the conformation of a short peptide. A CAVEAT search of the Cambridge Structural Database suggested that peptide complexes of the Cu(II) ion may adopt the appropriate conformation to mimic the Trp-Arg-Tyr beta-turn segment of tendamistat, a proteinaceous inhibitor of alpha-amylase. Complexation of tetrapeptides containing this sequence with the Cu(II) ion leads to an average enhancement of 200-fold in their ability to inhibit the enzyme. Whereas the free peptides Gly-Trp-Arg-Tyr (GWRY), Gly-Trp-Arg-D-Tyr (GWRy), and Trp-Arg-Tyr-Gly (WRYG) exhibit inhibition constants K-1(L) in the range of 680 to 750 mu M, those for their Cu(II) complexes, K-i(CuL), were found to be 2.4-5.9 mu M. Since Cu(II) ion is itself a potent inhibitor of cl-amylase (K-i(Cu) = 1 mu M), several methods were used to determine the inhibition constants of the peptide complexes. The most effective employed fixed concentrations of both Cu(II) (20 mu M) and tetrapeptides (0.4-2.0 mM), with variation of the ratio of the subject tetrapeptide to a non-inhibitory tetrapeptide like tetraglycine (GGGG) or Gly-Gly-Phe-Leu (GGFL). Under these conditions, almost all of the copper ion is in the form of a peptide complex, and the concentration of the inhibitory complex itself is determined by the mole ratio of the peptides and their complexation constants, K. Nonlinear regression analysis of the data allowed consistent values of K-i(CuL) as well as K to be determined for each peptide. The large enhancement in affinity induced by copper complexation suggests that the metal ion templates the peptides and increases the proportion present in the bioactive beta-turn conformation.