When a protein binds to DNA, the surface atoms of the protein interact with those of the DNA. If one imagines isolating all of the contacts to one region, defined as the binding site, then one can also imagine the total energy of interaction involved in binding to the site. This is referred to as the intrinsic binding energy. In a two site system, there are two such binding sites, and thus two intrinsic binding energies (interactions 1 and 2 in the picture).

It is also possible that binding at one site affects the interactions of binding at the other site, and vice versa. In such a case, binding of ligand to the first site either inhibits (negative cooperativity) or enhances (positive cooperativity) binding of the second ligand. The reduced or increased energy of binding can come from changes in DNA structure upon binding the first ligand, or from new contacts for the second protein that are located on the first one (for example, interaction 3 in the picture).

(The image was a particular view of 3cro.pdb exported from RasMol and edited in Adobe Photoshop.)