Toward polarizable AMOEBA thermodynamics at fixed charge efficiency using a dual force field approach: application to organic crystals

• Published in: Physical chemistry chemical physics : PCCP 2016-11, Vol.18 (44), p.3313-3322
• Main Authors: Nessler, Ian J, Litman, Jacob M, Schnieders, Michael J
• Format: Article
• Language: English
• Subjects: Amoeba; Crystal structure; Crystals; Deposition; Errors; Mathematical models; Sampling; Thermodynamics
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/c6cp02595a

First principles prediction of the structure, thermodynamics and solubility of organic molecular crystals, which play a central role in chemical, material, pharmaceutical and engineering sciences, challenges both potential energy functions and sampling methodologies. Here we calculate absolute crystal deposition thermodynamics using a novel dual force field approach whose goal is to maintain the accuracy of advanced multipole force fields ( e.g. the polarizable AMOEBA model) while performing more than 95% of the sampling in an inexpensive fixed charge (FC) force field ( e.g. OPLS-AA). Absolute crystal sublimation/deposition phase transition free energies were determined using an alchemical path that grows the crystalline state from a vapor reference state based on sampling with the OPLS-AA force field, followed by dual force field thermodynamic corrections to change between FC and AMOEBA resolutions at both end states (we denote the three step path as AMOEBA/FC). Importantly, whereas the phase transition requires on the order of 200 ns of sampling per compound, only 5 ns of sampling was needed for the dual force field thermodynamic corrections to reach a mean statistical uncertainty of 0.05 kcal mol −1 . For five organic compounds, the mean unsigned error between direct use of AMOEBA and the AMOEBA/FC dual force field path was only 0.2 kcal mol −1 and not statistically significant. Compared to experimental deposition thermodynamics, the mean unsigned error for AMOEBA/FC (1.4 kcal mol −1 ) was more than a factor of two smaller than uncorrected OPLS-AA (3.2 kcal mol −1 ). Overall, the dual force field thermodynamic corrections reduced condensed phase sampling in the expensive force field by a factor of 40, and may prove useful for protein stability or binding thermodynamics in the future. First principles prediction of the structure, thermodynamics and solubility of organic molecular crystals, which play a central role in chemical, material, pharmaceutical and engineering sciences, challenges both potential energy functions and sampling methodologies.