Absolute organic crystal thermodynamics: Growth of the asymmetric unit into a crystal via alchemy

Jooyeon Park, Ian Nessler, Brian McClain, Dainius MacIkenas, Jonas Baltrusaitis, Michael J. Schnieders

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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 ΔGsolubility° = ΔGsub° + ΔGsolv°. 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 ΔGdep° = - ΔGsub° = - kBT ln(Vc/Vg) + ΔGAU + ΔGAU→UC as the sum of an entropic term to account for compressing a vapor at 1 M standard state (Vg) into the molar volume of the crystal (Vc), where kB is Boltzmann's constant and T is temperature in degrees Kelvin, plus two simulation steps. In the first simulation step, the deposition free energy ΔG AU for a system composed of only NAU asymmetric unit (AU) molecule(s) is computed beginning from an arbitrary conformation in vacuum. In the second simulation step, the change in free energy ΔG AU→UC to expand the asymmetric unit degrees of freedom into a unit cell (UC) composed of NUC 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.

Original languageEnglish
Pages (from-to)2781-2791
Number of pages11
JournalJournal of Chemical Theory and Computation
Volume10
Issue number7
DOIs
StatePublished - 8 Jul 2014

Fingerprint

Dive into the research topics of 'Absolute organic crystal thermodynamics: Growth of the asymmetric unit into a crystal via alchemy'. Together they form a unique fingerprint.

Cite this