The Structure, Thermodynamics, and Solubility of Organic Crystals from Simulation with a Polarizable Force Field

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• 作者：Michael J. Schnieders ; Jonas Baltrusaitis ; Yue Shi ; Gaurav Chattree ; Lianqing Zheng ; Wei Yang ; Pengyu Ren
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2012
• 出版时间：May 8, 2012
• 年：2012
• 卷：8
• 期：5
• 页码：1721-1736
• 全文大小：630K
• 年卷期：v.8,no.5(May 8, 2012)
• ISSN：1549-9626

文摘

An important unsolved problem in materials science is prediction of the thermodynamic stability of organic crystals and their solubility from first principles. Solubility can be defined as the saturating concentration of a molecule within a liquid solvent, where the physical picture is of solvated molecules in equilibrium with their solid phase. Despite the importance of solubility in determining the oral bioavailability of pharmaceuticals, prediction tools are currently limited to quantitative structure鈥損roperty relationships that are fit to experimental solubility measurements. For the first time, we describe a consistent procedure for the prediction of the structure, thermodynamic stability, and solubility of organic crystals from molecular dynamics simulations using the polarizable multipole AMOEBA force field. Our approach is based on 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, which are computed via the orthogonal space random walk (OSRW) sampling strategy. Application to the n-alkylamides series from acetamide through octanamide was selected due to the dependence of their solubility on both amide hydrogen bonding and the hydrophobic effect, which are each fundamental to protein structure and solubility. On average, the calculated absolute standard state solubility free energies are accurate to within 1.1 kcal/mol. The experimental trend of decreasing solubility as a function of n-alkylamide chain length is recapitulated by the increasing stability of the crystalline state and to a lesser degree by decreasing favorability of solvation (i.e., the hydrophobic effect). Our results suggest that coupling the polarizable AMOEBA force field with an orthogonal space based free energy algorithm, as implemented in the program Force Field X, is a consistent procedure for predicting the structure, thermodynamic stability, and solubility of organic crystals.