EF-hands are Ca(2+) binding motifs that are widely distributed throughout the entire living organism kingdom. At present, relatively little is known at a quantum mechanical level about the mechanisms that allow Ca(2+) to be recognized specifically by EF-hands and to induce a conformational switch from a compact ("closed") conformation to an "open" state that exposes a large patch of hydrophobic residues. Here, we present a study of NMR (15)N chemical shifts based on ab initio quantum mechanical calculations carried out on a minimalist model system linking both Ca(2+) binding sites across the beta-sheet of an EF-hand domain. Calculated and experimentally determined chemical shift changes are correlated with structural changes induced upon metal binding. The effect of Ca(2+) binding on these (15)N shifts can be dissected into two main contributions: one from pi-polarization of beta-sheet amide groups and the other from rotation of an isoleucine side chain. By correlating this description with experimental evidence, different polarization states for the beta-sheet amide groups were identified and linked to the overall conformation of different EF-hand domains. When all four beta-sheet amide groups are polarized, the ab initio calculations in our model indicate a cooperative stabilization effect due to the establishment of a circular network of donor-acceptor interactions connecting the two Ca(2+) ions across the beta-sheet. The emerging hypothesis from our analysis is that this cooperative network of interactions is essential for stabilizing the "open" conformation of an EF-hand domain.