THE STATISTICAL-THERMODYNAMIC BASIS FOR COMPUTATION OF BINDING AFFINITIES - A CRITICAL-REVIEW

Although the statistical thermodynamics of noncovalent binding has bee n considered in a number of theoretical papers, few methods of computi ng binding affinities are derived explicitly from this underlying theo ry. This has contributed to uncertainty and controversy in certain are as. This article therefore reviews and extends the connections of some important computational methods with the underlying statistical therm odynamics. A derivation of the standard free energy of binding forms t he basis of this review. This derivation should be useful in formulati ng novel computational methods for predicting binding affinities. It a lso permits several important points to be established. For example, i t is found that the double-annihilation method of computing binding en ergy does not yield the standard free energy of binding, but can be mo dified to yield this quantity. The derivation also makes it possible t o define clearly the changes in translational, rotational, configurati onal, and solvent entropy upon binding. It is argued that molecular ma ss has a negligible effect upon the standard free energy of binding fo r biomolecular systems, and that the cratic entropy defined by Gurney is not a useful concept. In addition, the use of continuum models of t he solvent in binding calculations is reviewed, and a formalism is pre sented for incorporating a limited number of solvent molecules explici tly.