We report herein a theoretical calculation of the ion atmosphere contribution to the free energy of association for a protein-DNA complex based on Monte Carlo computer simulations and thermodynamic perturbation theory. The system considered is the dimer of the amino-terminal fragment of the XcI repressor in a complex with a 17 base pair oligonucleotide of DNA, based on the crystal structure of Pabo and Sauer. Only the movements of the small ions (sodium and chloride ions) are considered explicitly, with solvent water modeled as a dielectric continuum (a 'primitive model"). The free energies are determined as a function of both distance of separation between the protein and the DNA, each of which is fixed in its respective crystal geometry, and ionic strength at a temperature of 298 K. Results of our simulations indicate that the ion atmosphere contribution to the free energy of association is favorable only at short distances of separation and is at a maximum when the protein approaches the DNA from a distance of -7 A. This distance corresponds to the radius of the shroud of condensed counterions around B-DNA. At larger distances of separation between the protein and the DNA, the uncondensed diffuse ionic cloud opposes complexation. The effect known as 'counterion release" in the context of DNA-ligand association appears to be short-ranged and a property of the condensed counterions only. Introduction The nature of protein-DNA interactions is currently a subject of considerable research interest in molecular biophysics.'-5 (1) Pabo, C. 0.; Sauer, R. T. Annu. Reu. Blochem. 1984, 53, 293-321. Crystal structures of the protein-nucleic acid complexes reported in the recent literatureb12 and the concurrent 2D N M R st~dies'~-' ' (2) Matthews, B. W. Narure 1988, 335, 294-295. (3) Travers, A. A. Annu. Rev. Blochem. 1989, 58,421452. 0002-7863/91/1513-5211%02.50/0