Direct Calculation of Octanol-Water Partition Coefficients From Adaptive Force Bias Molecular Dynamics Simulations

Tuesday, October 18, 2011: 3:35 PM
Conrad B (Hilton Minneapolis)
Navendu Bhatnagar, Chemical Engineering, Wayne State University, Detroit, MI and Jeffrey J. Potoff, Chemcial Engineering and Materials Science, Wayne State University, Detroit, MI

Partition coefficient (log Kow) of a solute between 1-octanol and water [1] is an important parameter  to predict a spectrum of solute properties such as pharmacokinetic characteristics in biological systems, drug partitioning in biophases, bioaccumalation [2,3], and is also used as a key input in quantitative structure-activity relationships (QSAR) [4].  Several techniques have been devised over the years for prediction of log Kow which include experimental [5], semi-empirical [6], and QSAR based procedures. However, experimental methods are expensive and time consuming, QSAR is relatively fast but produces inaccurate results for molecules which are dissimilar to the ones in training set [4].  Molecular simulations are an effective tool for the determination of free energy differences that may be used to determine log Kow [7]. Free energy perturbation (FEP) and thermodynamic integration (TI) [8] in conjunction with Monte Carlo (MC) [9,10] or molecular dynamics (MD) [11] simulations have been used extensively to determine free energies of solvation.  Both free energy perturbation and thermodynamic integration are limited, though, by the need for a reference solute, which may create both systematic and statistical errors in the determination of octanol-water partition coefficients.

In this work, free energy change and log Kow is predicted for transfer of n-alkanes across the 1-octanol|water and the air|water interface using a recently developed method known as adaptive biasing force (ABF) [12], which is based on unconstrained molecular dynamics simulations.  Calculations are performed by using two separate approaches, where in the first one the solute is transferred directly from water to 1-octanol resulting providing the absolute free energy difference directly whereas in the second approach, a thermodynamic cycle is constructed and solute is transferred from water and 1-octanol phases to vapor phase in separate calculations resulting in relative free energy difference.  Molecular dynamics simulations are performed with NAMD version 2.7b3 using united atom TraPPE [13] and the all atom CHARMM27 force field at a constant temperature of 298.0 K.   Predictions from the ABF method are in close agreement with previous calculations that used thermodynamic integration [11].   



  1. Hansch, C.; Fujita, T. J. Am. Chem. Soc. (1964), 86, 1616.
  2. Sangster, J. Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry, John Wiley & Sons, 1997
  3. Connell, D. W. Bioaccumalation of Xenobiotic Compounds, CRC Press, 1990.
  4. Hansch, C.; Leo, A. Exploring QSAR: Fundamentals and Applications in Chemistry and Biology, ACS, 1995.
  5. Bergstrom, C. A. S.; Norinder, U.; Luthmann, K.; Artursson, P. Pharmaceut. Res.,(2002), 19, 182.
  6. Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. (1971), 71, 525.
  7. Jorgensen, W.; Briggs, J.; Contreras, M. J. Phys. Chem. (1990), 94, 1683.
  8. Kirkwood, J. G. J. Chem. Phys. (1935), 3, 300.
  9. Chipot, C.; Pohorille, A. Free Energy Calculations: Theory and Applications in Chemistry and Biology, Springer, 2007.
  10. Chen, B.; Siepmann, J.I. J. Am. Chem. Soc. (2000), 122, 6464.
  11. Garrido, N.M; Queimada, A.J.; Jorge, M.;Macedo, E.A.; Economou, I.G. J. Chem. Theory Comput. (2009), 5, 2436.
  12. Darve, E.; Pohorille, A. Mol. Simul. (2002), 28, 113.
  13. Martin, M.G.; Siepmann, J.I. J. Phys. Chem. B (1998), 102, 2569.

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