I will discuss computational calorimetry, the use of explicit solvent simulations to compute binding free energies and enthalpies at a numerical precision comparable to that of experiment. At this level of precision, discrepancies between computation and experiment should be attributable primarily to force field issues, and our comparisons with experiment keep turning up unexpected results. For example, for a nonionized host-guest system, the salt-dependence of the binding enthalpy proves highly sensitive to the water model used. I will argue that host-guest binding thermodynamics represent a trove of experimental data which are now computationally accessible and can be of great value to test and improve force fields. Such efforts may be enhanced by the application of sensitivity analysis, which we have shown can be used to estimate the first derivatives of host-guest binding free energies and enthalpies to any force field parameter of interest.<br/>Time permitting, I also plan to present a recent extension of the Grid Inhomogeneous Solvation Theory (GIST) approach to studying binding-site water. This extension now enables three-dimensional visualization of the second-order (water-water) contribution to the translational entropy as a function of position, and offers insights into the physical basis for this term.

Computational thermodynamics of noncovalent binding

251st National Meeting (2016)

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