Absolute Organic Crystal Thermodynamics: Growth of the Asymmetric Unit into a Crystal via Alchemy

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• 作者：Jooyeon Park ; Ian Nessler ; Brian McClain ; Dainius Macikenas ; Jonas Baltrusaitis ; Michael J. Schnieders
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2014
• 出版时间：July 8, 2014
• 年：2014
• 卷：10
• 期：7
• 页码：2781-2791
• 全文大小：437K
• ISSN：1549-9626

文摘

The solubility of organic molecules is of critical importance to the pharmaceutical industry; however, robust computational methods to predict this quantity from first-principles are lacking. Solubility can be computed from a thermodynamic cycle that decomposes standard state solubility into the sum of solid鈥搗apor sublimation and vapor鈥搇iquid solvation free energies 螖G_solubility^掳 = 螖G_sub^掳 + 螖G_solv^掳. Over the past few decades, alchemical simulation methods to compute solvation free energy using classical force fields have become widely used. However, analogous methods for determining the free energy of the sublimation/deposition phase transition are currently limited by the necessity of a priori knowledge of the atomic coordinates of the crystal. Here, we describe progress toward an alternative scheme based on growth of the asymmetric unit into a crystal via alchemy (GAUCHE). GAUCHE computes deposition free energy 螖G_dep^掳 = 鈭捨?i>G_sub^掳 = 鈭?i>k_BT ln(V_c/V_g) + 螖G_AU + 螖G_AU鈫扷C as the sum of an entropic term to account for compressing a vapor at 1 M standard state (V_g) into the molar volume of the crystal (V_c), where k_B is Boltzmann鈥檚 constant and T is temperature in degrees Kelvin, plus two simulation steps. In the first simulation step, the deposition free energy 螖G_AU for a system composed of only N_AU asymmetric unit (AU) molecule(s) is computed beginning from an arbitrary conformation in vacuum. In the second simulation step, the change in free energy 螖G_AU鈫扷C to expand the asymmetric unit degrees of freedom into a unit cell (UC) composed of N_UC independent molecules is computed. This latter step accounts for the favorable free energy of removing the constraint that every symmetry mate of the asymmetric unit has an identical conformation and intermolecular interactions. The current work is based on NVT simulations, which requires knowledge of the crystal space group and unit cell parameters from experiment, but not a priori knowledge of crystalline atomic coordinates. GAUCHE was applied to 5 organic molecules whose sublimation free energy has been measured experimentally, based on the polarizable AMOEBA force field and more than a microsecond of sampling per compound in the program Force Field X. The mean unsigned and RMS errors were only 1.6 and 1.7 kcal/mol, respectively, which indicates that GAUCHE is capable of accurate prediction of absolute sublimation thermodynamics.