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

作者：Park Jooyeon; Nessler Ian; McClain Brian; Macikenas Dainius; Baltrusaitis Jonas; Schnieders Michael J^*

来源：Journal of Chemical Theory and Computation, 2014, 10(7): 2781-2791.

DOI：10.1021/ct500180m

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 vapor sublimation and vapor liquid solvation free energies Delta G degrees(solubility) = Delta G degrees sub + Delta G degrees(solv). 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 Delta G degrees(dep) = -Delta G degrees(sub) = -k(B)T ln(V-c/V-g) + Delta G(AU) + Delta G(AU -%26gt; UC) 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,), where k(B) is Boltzmann%26apos;s constant and T is temperature in degrees Kelvin, plus two simulation steps. In the first simulation step, the deposition free energy Delta 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 Delta G(AU -%26gt; UC) 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.

• 出版日期2014-7