Journal article
The Structure, Thermodynamics and Solubility of Organic Crystals from Simulation with a Polarizable Force Field
Journal of chemical theory and computation, Vol.8(5), pp.1721-1736
05/08/2012
DOI: 10.1021/ct300035u
PMCID: PMC3348590
PMID: 22582032
Abstract
An important unsolved problem in materials science is prediction of the thermodynamic stability of organic crystals and their solubility from first principles. Solubility can be defined as the saturating concentration of a molecule within a liquid solvent, where the physical picture is of solvated molecules in equilibrium with their solid phase. Despite the importance of solubility in determining the oral bioavailability of pharmaceuticals, prediction tools are currently limited to quantitative structure–property relationships that are fit to experimental solubility measurements. For the first time, we describe a consistent procedure for the prediction of the structure, thermodynamic stability and solubility of organic crystals from molecular dynamics simulations using the polarizable multipole AMOEBA force field. Our approach is based on a thermodynamic cycle that decomposes standard state solubility into the sum of solid-vapor sublimation and vapor-liquid solvation free energies
Δ
G
solubility
o
=
Δ
G
sub
o
+
Δ
G
solv
o
, which are computed via the orthogonal space random walk (OSRW) sampling strategy. Application to the
n
-alkylamides series from aeetamide through octanamide was selected due to the dependence of their solubility on both amide hydrogen bonding and the hydrophobic effect, which are each fundamental to protein structure and solubility. On average, the calculated absolute standard state solubility free energies are accurate to within 1.1 kcal/mol. The experimental trend of decreasing solubility as a function of
n
-alkylamide chain length is recapitulated by the increasing stability of the crystalline 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, thermodynamic stability and solubility of organic crystals.
Details
- Title: Subtitle
- The Structure, Thermodynamics and Solubility of Organic Crystals from Simulation with a Polarizable Force Field
- Creators
- Michael J Schnieders - Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712Jonas Baltrusaitis - Departments of Chemistry and Chemical/Biochemical Engineering, University of Iowa, Iowa City, IA, 52242Yue Shi - Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712Gaurav Chattree - Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712Lianqing Zheng - The Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306Wei Yang - The Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306Pengyu Ren - Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712
- Resource Type
- Journal article
- Publication Details
- Journal of chemical theory and computation, Vol.8(5), pp.1721-1736
- DOI
- 10.1021/ct300035u
- PMID
- 22582032
- PMCID
- PMC3348590
- NLM abbreviation
- J Chem Theory Comput
- ISSN
- 1549-9618
- eISSN
- 1549-9626
- Grant note
- R01 GM079686-05 || GM / National Institute of General Medical Sciences : NIGMS
- Language
- English
- Date published
- 05/08/2012
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology
- Record Identifier
- 9984024500802771
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