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

Knowledge of the underlying free energy of biologically active species in solution is crucial to understanding their thermodynamic phase behavior, which is essential for rational drug design. We will present an efficient expanded ensemble method to calculate the solvation free energy of small molecules with complex topologies by molecular dynamics simulation. By computing the solvation free energy of ibuprofen in water and small alcohols at 300 K and 1 bar and comparing to reference simulation results, we will validate the methodology. In the present study, the carboxylic acid functional group of ibuprofen is subject to free energy barriers of rotation of 14-20 k_BT, leading to sampling difficulties with conventional molecular dynamics simulations. While several advances have been made to overcome such weaknesses, we will demonstrate how this shortcoming is easily overcome by using an expanded ensemble methodology to facilitate the sampling of phase space.