Treating Entropy and Conformational Changes in Implicit Solvent Simulations of Small Molecules

Implicit solvent models are increasingly popular for estimating aqueous solvation (hydration) free energies in
molecular simulations and other applications. In many cases, parameters for these models are derived to
reproduce experimental values for small molecule hydration free energies. Often, these hydration free energies
are computed for a single solute conformation, neglecting solute conformational changes upon solvation.
Here, we incorporate these effects using alchemical free energy methods. We find significant errors when
hydration free energies are estimated using only a single solute conformation, even for relatively small, simple,
rigid solutes. For example, we find conformational entropy (TΔS) changes of up to 2.3 kcal/mol upon hydration.
Interestingly, these changes in conformational entropy correlate poorly (R2 = 0.03) with the number of rotatable
bonds. The present study illustrates that implicit solvent modeling can be improved by eliminating the
approximation that solutes are rigid.