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Multiple aromatic amine insertion mediated by a diiron complex
International audienc
Absolute Organic Crystal Thermodynamics: Growth of the Asymmetric Unit into a Crystal via Alchemy
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 Δ<i>G</i><sub>solubility</sub><sup>°</sup> = Δ<i>G</i><sub>sub</sub><sup>°</sup> + Δ<i>G</i><sub>solv</sub><sup>°</sup>. 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 <u>g</u>rowth of the <u>a</u>symmetric <u>u</u>nit into a <u>c</u>rystal via alc<u>he</u>my (GAUCHE). GAUCHE computes deposition free energy
Δ<i>G</i><sub>dep</sub><sup>°</sup> = −Δ<i>G</i><sub>sub</sub><sup>°</sup> = −<i>k</i><sub>B</sub><i>T</i> lnÂ(<i>V</i><sub>c</sub>/<i>V</i><sub>g</sub>) + Δ<i>G</i><sub>AU</sub> + Δ<i>G</i><sub>AU→UC</sub> as
the sum of an entropic term to account for compressing a vapor at
1 M standard state (<i>V</i><sub>g</sub>) into the molar
volume of the crystal (<i>V</i><sub>c</sub>), where <i>k</i><sub>B</sub> is Boltzmann’s constant and <i>T</i> is temperature in degrees Kelvin, plus two simulation
steps. In the first simulation step, the deposition free energy Δ<i>G</i><sub>AU</sub> for a system composed of only <i>N</i><sub>AU</sub> asymmetric unit (AU) molecule(s) is computed beginning
from an arbitrary conformation in vacuum. In the second simulation
step, the change in free energy Δ<i>G</i><sub>AU→UC</sub> to expand the asymmetric unit degrees of freedom into a unit cell
(UC) composed of <i>N</i><sub>UC</sub> 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
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