An unsolved challenge in modeling the structure, thermodynamics and solubility of organic drug crystals is to simultaneously achieve a 1) highly accurate description of molecular forces and 2) the computational efficiency needed to thoroughly sample molecular conformations. In this work we describe a solution based on combining the strengths of two complementary models of intermolecular forces. The first model maintains speed by describing atomic electrostatics using simple fixed partial charges, while the second model achieves energetic precision by using a polarizable atomic multipole force field called 'AMOEBA'. The key to our approach is a rigorous statistical mechanics algorithm that allows the vast majority of conformational sampling to be done using the cheaper model by taking advantage of the path independence of thermodynamics. Specifically, the beginning and ending states of the simulation are described by the precise force field, while the intermediate transitions are described by the inexpensive model with the Force Field X software (http://ffx.biochem.uiowa.edu). We demonstrate this “dual force field” approach, which accelerates our molecular dynamics sampling by a factor of 10 to 100x, by calculating the thermodynamics stability for a series of organic crystals of pharmaceutical compounds.

May the (dual) force be with you: Polarizable AMOEBA free energies at the speed of fixed charge force fields

250th National Meeting (2015)

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