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

The soly. of org. mols. is of crit. importance to the pharmaceutical industry; however, robust computational methods to predict this quantity from first-principles are lacking. Soly. can be computed from a thermodn. cycle that decomps. std. state soly. into the sum of solid-vapor sublimation and vapor-liq. solvation free energies ΔG°solubility = ΔG°sub + ΔG°solv. Over the past few decades, alchem. simulation methods to compute solvation free energy using classical force fields have become widely used. However, analogous methods for detg. the free energy of the sublimation/deposition phase transition are currently limited by the necessity of a priori knowledge of the at. coordinates of the crystal. The authors describe progress toward an alternative scheme based on growth of the asym. unit into a crystal via alchemy (GAUCHE). GAUCHE computes deposition free energy ΔG°dep = -ΔG°sub = -kBT ln(Vc/Vg) + ΔGAU + ΔGAU→UC as the sum of an entropic term to account for compressing a vapor at 1 M std. state (Vg) into the molar volume of the crystal (Vc), where kB is Boltzmann's const. and T is temp. in K, plus two simulation steps. In the first simulation step, the deposition free energy ΔGAU for a system composed of only NAU asym. unit (AU) mol.(s) is computed beginning from an arbitrary conformation in vacuum. In the second simulation step, the change in free energy ΔGAU→UC to expand the asym. unit degrees of freedom into a unit cell (UC) composed of NUC independent mols. is computed. This latter step accounts for the favorable free energy of removing the constraint that every symmetry mate of the asym. unit has an identical conformation and intermol. interactions. The current work is based on NVT simulations, which requires knowledge of the crystal space group and unit cell parameters from expt., but not a priori knowledge of cryst. at. coordinates. GAUCHE was applied to 5 org. mols. whose sublimation free energy has been measured exptl., based on the polarizable AMOEBA force field and more than a microsecond of sampling per compd. in the program Force Field X. The mean unsigned and RMS errors were only 1.6 and 1.7 kcal/mol, resp., which indicates that GAUCHE is capable of accurate prediction of abs. sublimation thermodn. [on SciFinder(R)]