Contribution of translational and rotational motions to molecular association in aqueous solution

Much uncertainty and controversy exist regarding the estimation of the enth alpy, entropy, and free energy of overall translational and rotational moti ons of solute molecules in aqueous solutions, quantities that are crucial t o the understanding of molecular association/recognition processes and stru cture-based drug design. A critique of the literature on this topic is give n that leads to a classification of the various views. The major stumbling block to experimentally determining the translational/rotational enthalpy a nd entropy is the elimination of vibrational perturbations from the measure d effects. A solution to this problem, based on a combination of energy equ i-partition and enthalpy-entropy compensation, is proposed and subjected to verification. This method is then applied to analyze experimental data on the dissociation/unfolding of dimeric proteins. For one translational/rotat ional unit at 1 M standard state in aqueous solution, the results for entha lpy (H(tr)degrees), entropy (S(tr)degrees), and free energy (G(tr)degrees) are H(tr)degrees = 4.5 +/- 1.5RT, S(tr)degrees = 5 +/- 4R, and G(tr)degrees = 0 +/- 5RT. Therefore, the overall translational and rotational motions m ake negligible contribution to binding affinity (free energy) in aqueous so lutions at 1 M standard state.