Small Molecule Solvation Free Energy: Enhanced Conformational Sampling Using Expanded Ensemble Molecular Dynamics Simulation

We present an efficient expanded ensemble molecular dynamics method to calculate the solvation free energy (or residual chemical potential) of small molecules with complex topologies. The methodology is validated by computing the solvation free energy of ibuprofen in water, methanol, and ethanol at 300 K and 1 bar and comparing to reference simulation results using Bennett's acceptance ratio method. Difficulties with ibuprofen using conventional molecular dynamics methods stem from an inadequate sampling of the carboxylic acid functional group, which, for the present study, is subject to free energy barriers of rotation of 14-20 kBT. While several advances have been made to overcome such weaknesses, we demonstrate how this shortcoming is easily overcome by using an expanded ensemble methodology to facilitate conformational sampling. Not only does the method enhance conformational sampling but it also boosts the rate of exploration of the configurational phase space and requires only a single simulation to calculate the solvation free energy. Agreement between the expanded ensemble and the reference calculations is good for all three solvents, with the reported uncertainties of the expanded ensemble being comparable to the uncertainties of the reference calculations, while requiring less simulation time; the reduced simulation time demonstrates the improved performance gained from the expanded ensemble method.