We present a free-energy-based methodology to enable convenient numerical calculation of the solubility of general molecular crystals at arbitrary thermodynamic conditions, exemplified by naphthalene at varying temperatures and pressures. The solubility of a substance can be estimated from its absolute free energy in the crystalline phase and excess solvation free energy in the solution. The methodology is based on standard alchemical free energy methods such as thermodynamic integration and free energy perturbation, and includes a systematic extension of the original Einstein crystal method to calculates the absolute crystal free energies and a newly designed flexible cavity method that can give accurate excess solvation free energies. Via classical molecular dynamic simulations, we show that our approach successfully calculate the solubility of OPLS-AA-based naphthalene in SPC water in good agreement with experimental data. Because the procedure is simple and generic, and designed to make use only of readily available open-source software, the methodology should provide a powerful tool for realizing universal solubility prediction.

Universal methodology to predict solubility via molecular dynamics simulations of naphthalene

256th National Meeting (2018)

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