Estimating binding constants - The hydrophobic effect and cooperativity

The reliable estimation of binding constants by computational means for drugs binding to receptors represents one of the major challenges in molecular recognition. Many approaches to this problem have relied on the partitioning of binding free energy according to each of the interactions which are made or broken on binding, e.g., hydrogen bonds, salt bridges, pi-pi interactions, or the hydrophobic effect. With particular reference to the hydrophobic effect, we illustrate how such partitioning ignores one of the fundamental properties of systems of non-covalent interactions, namely that of cooperativity. This leads to estimates for the free energy benefit of the hydrophobic effect which vary according to the method of determination used, and whether the system in which the measurements are taken exhibits cooperativity. The context dependence of the magnitude of the hydrophobic effect illustrates the problem associated with considering weak interactions in isolation from the system in which they occur. The approach of partitioning binding affinities can be very useful, but until the problem of cooperativity can be better addressed by computational chemists, there remains the possibility that attempts to estimate at least some binding constants will unfortunately be seriously flawed.