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

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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.

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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.

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Correspondence to Samuel Genheden.

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Genheden, S., Cabedo Martinez, A.I., Criddle, M.P. et al. Extensive all-atom Monte Carlo sampling and QM/MM corrections in the SAMPL4 hydration free energy challenge. J Comput Aided Mol Des 28, 187–200 (2014).

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