Calculating distribution coefficients based on multi-scale free energy simulations: an evaluation of MM and QM/MM explicit solvent simulations of water-cyclohexane transfer in the SAMPL5 challenge

J Comput Aided Mol Des. 2016 Nov;30(11):989-1006. doi: 10.1007/s10822-016-9936-x. Epub 2016 Aug 30.


One of the central aspects of biomolecular recognition is the hydrophobic effect, which is experimentally evaluated by measuring the distribution coefficients of compounds between polar and apolar phases. We use our predictions of the distribution coefficients between water and cyclohexane from the SAMPL5 challenge to estimate the hydrophobicity of different explicit solvent simulation techniques. Based on molecular dynamics trajectories with the CHARMM General Force Field, we compare pure molecular mechanics (MM) with quantum-mechanical (QM) calculations based on QM/MM schemes that treat the solvent at the MM level. We perform QM/MM with both density functional theory (BLYP) and semi-empirical methods (OM1, OM2, OM3, PM3). The calculations also serve to test the sensitivity of partition coefficients to solute polarizability as well as the interplay of the quantum-mechanical region with the fixed-charge molecular mechanics environment. Our results indicate that QM/MM with both BLYP and OM2 outperforms pure MM. However, this observation is limited to a subset of cases where convergence of the free energy can be achieved.

Keywords: Cyclohexane; Distribution coefficient; Explicit solvent; Multi-scale free energy simulations; Partition coefficient; Water.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation*
  • Cyclohexanes / chemistry*
  • Models, Chemical
  • Molecular Structure
  • Pharmaceutical Preparations / chemistry*
  • Quantum Theory
  • Solubility
  • Solvents / chemistry*
  • Thermodynamics
  • Water / chemistry*


  • Cyclohexanes
  • Pharmaceutical Preparations
  • Solvents
  • Water
  • Cyclohexane