@article {76,
	title = {Absolute Organic Crystal Thermodynamics: Growth of the Asymmetric Unit into a Crystal via Alchemy.},
	journal = {Journal of Chemical Theory and Computation},
	volume = {10},
	year = {2014},
	note = {CAPLUS AN 2014:831069(Journal; Online Computer File)},
	pages = {2781 - 2791},
	publisher = {American Chemical Society},
	abstract = {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{\textdegree}solubility = ΔG{\textdegree}sub + ΔG{\textdegree}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{\textdegree}dep = -ΔG{\textdegree}sub = -kBT ln(Vc/Vg) + ΔGAU + ΔGAU{\textrightarrow}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{\textquoteright}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{\textrightarrow}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)]},
	keywords = {abs org crystal thermodn growth asym unit crystal alchemy, simulation free energy soly thermodn cycle sublimation solvation},
	isbn = {1549-9618},
	author = {Park, Jooyeon and Nessler, Ian and McClain, Brian and Macikenas, Dainius and Baltrusaitis, Jonas and Schnieders, Michael J.}
}
@article {146,
	title = {The Structure, Thermodynamics, and Solubility of Organic Crystals from Simulation with a Polarizable Force Field.},
	journal = {Journal of Chemical Theory and Computation},
	volume = {8},
	year = {2012},
	note = {CAPLUS AN 2012:553598(Journal; Online Computer File)},
	month = {2012///},
	pages = {1721 - 1736},
	publisher = {American Chemical Society},
	abstract = {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{\textdegree} = ΔGsub{\textdegree} + ΔGsolv{\textdegree}, 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)]},
	keywords = {structure thermodn soly org crystal polarizable force field simulation},
	isbn = {1549-9618},
	author = {Schnieders, Michael J. and Baltrusaitis, Jonas and Shi, Yue and Chattree, Gaurav and Zheng, Lianqing and Yang, Wei and Ren, Pengyu.}
}
