Predicting binding energetics from structure: Looking beyond Delta G degrees

Structure-based design of pharmaceuticals requires the ability to predict l igand affinity based on knowledge of structure. The primary term of interes t is the binding affinity constant, K, or the free energy of binding, Delta G degrees. It is common to attempt to predict Delta G degrees based on emp irically derived terms which represent common contributions such as the hyd rophobic effect, hydrogen bonding, and conformational entropy. Although the seapproaches have met with some success, when they fail it is difficult to know which parameter(s) need refinement. Confidence in these approaches is also limited by the fact that Delta G degrees typically is made up of compe nsating enthalpic and entropic terms, Delta H degrees and Delta S degrees, so that accurate prediction of a Delta G degrees value may be fortuitous an d may not indicate a reasonable understanding of the underlying relationshi p between structure and affinity. This is further complicated by the fact t hat both Delta H degrees and Delta S degrees are strongly temperature depen dent through the heat capacity change, Delta C-p. In order to avoid these d ifficulties, we attempt to use structural data to predict Delta H degrees, Delta S degrees, and Delta C-p, from which Delta G degrees can be calculate d as a function of temperature. The predictions are then compared to experi mentally determined values. These calculations have been applied to several systems by ourselves and others. Systems include the binding of angiotensi n II to an antibody, the dimerization of interleukin-8, and the binding of inhibitors to aspartic and serine proteases. Overall the calculations are v ery successful, and suggest that our understanding of the contributions of the hydrophobic effect, hydrogen bonding, and conformational entropy are qu ite good. Several of these systems show a strong dependence of the binding energetics on pH, indicative of changes in proton affinity of ionizable gro ups upon binding. It is critical to account for these protonation contribut ions to the binding energetics in order to assess the reliability of any co mputational prediction of energetics from structure. Methods have been deve loped for determining the energetics of proton binding using isothermal tit ration calorimetry. The availability of these methods provides a means of u nderstanding how protein structure can modify the pKa's of ionizable groups . This information will further add to our understanding of structural ener getic relationships and our ability accurately to predict binding affinitie s. (C) 1999 John Wiley & Sons. Inc.