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

An important unsolved problem in materials science is prediction of the thermodn. stability of org. crystals and their soly. from first principles. Soly. can be defined as the satg. concn. of a mol. within a liq. solvent, where the phys. picture is of solvated mols. in equil. with their solid phase. Despite the importance of soly. in detg. the oral bioavailability of pharmaceuticals, prediction tools are currently limited to quant. structure-property relationships that are fit to exptl. soly. measurements. For the first time, we describe a consistent procedure for the prediction of the structure, thermodn. stability, and soly. of org. crystals from mol. dynamics simulations using the polarizable multipole AMOEBA force field. Our approach is based on a thermodn. cycle that decomps. std. state soly. into the sum of solid-vapor sublimation and vapor-liq. solvation free energies ΔGsolubility° = ΔGsub° + ΔGsolv°, 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 soly. on both amide hydrogen bonding and the hydrophobic effect, which are each fundamental to protein structure and soly. On av., the calcd. abs. std. state soly. free energies are accurate to within 1.1 kcal/mol. The exptl. trend of decreasing soly. as a function of n-alkylamide chain length is recapitulated by the increasing stability of the cryst. 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, thermodn. stability, and soly. of org. crystals. [on SciFinder(R)]