Journal of Computer-Aided Molecular Design

, Volume 28, Issue 3, pp 187–200 | Cite as

Extensive all-atom Monte Carlo sampling and QM/MM corrections in the SAMPL4 hydration free energy challenge

  • Samuel Genheden
  • Ana I. Cabedo Martinez
  • Michael P. Criddle
  • Jonathan W. Essex


We present our predictions for the SAMPL4 hydration free energy challenge. Extensive all-atom Monte Carlo simulations were employed to sample the compounds in explicit solvent. While the focus of our study was to demonstrate well-converged and reproducible free energies, we attempted to address the deficiencies in the general Amber force field force field with a simple QM/MM correction. We show that by using multiple independent simulations, including different starting configurations, and enhanced sampling with parallel tempering, we can obtain well converged hydration free energies. Additional analysis using dihedral angle distributions, torsion-root mean square deviation plots and thermodynamic cycles support this assertion. We obtain a mean absolute deviation of 1.7 kcal mol−1 and a Kendall’s τ of 0.65 compared with experiment.


SAMPL4 Hydration free energy Monte Carlo simulation QM/MM corrections SMD 



For financial support we acknowledge AstraZeneca Pharmaceuticals and the Wenner-Gren foundations (SG) and Astex Pharmaceuticals (AICM). We acknowledge the use of the IRIDIS High Performance Computing Facility, and associated support services at the University of Southampton.

Supplementary material

10822_2014_9717_MOESM1_ESM.bz2 (36 kb)
Supplementary material 1 (BZ2 37 kb)
10822_2014_9717_MOESM2_ESM.bz2 (16 kb)
Supplementary material 2 (BZ2 17 kb)


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Samuel Genheden
    • 1
  • Ana I. Cabedo Martinez
    • 1
  • Michael P. Criddle
    • 1
  • Jonathan W. Essex
    • 1
  1. 1.School of ChemistryUniversity of SouthamptonHighfield, SouthamptonUK

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