Blind prediction of distribution in the SAMPL5 challenge with QM based protomer and pK a corrections

Frank C. Pickard*, Gerhard König, Florentina Tofoleanu, Juyong Lee, Andrew C. Simmonett, Yihan Shao, Jay W. Ponder, Bernard R. Brooks

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The computation of distribution coefficients between polar and apolar phases requires both an accurate characterization of transfer free energies between phases and proper accounting of ionization and protomerization. We present a protocol for accurately predicting partition coefficients between two immiscible phases, and then apply it to 53 drug-like molecules in the SAMPL5 blind prediction challenge. Our results combine implicit solvent QM calculations with classical MD simulations using the non-Boltzmann Bennett free energy estimator. The OLYP/DZP/SMD method yields predictions that have a small deviation from experiment (RMSD = 2.3 log D units), relative to other participants in the challenge. Our free energy corrections based on QM protomer and p Ka calculations increase the correlation between predicted and experimental distribution coefficients, for all methods used. Unfortunately, these corrections are overly hydrophilic, and fail to account for additional effects such as aggregation, water dragging and the presence of polar impurities in the apolar phase. We show that, although expensive, QM-NBB free energy calculations offer an accurate and robust method that is superior to standard MM and QM techniques alone.

Original languageEnglish
Pages (from-to)1087-1100
Number of pages14
JournalJournal of Computer-Aided Molecular Design
Issue number11
Early online date19 Sept 2016
Publication statusPublished - 1 Nov 2016


  • Distribution coefficients
  • Free energy
  • Implicit solvent
  • Non-Boltzmann Bennett
  • Partition coefficients
  • pK
  • Protomer
  • SAMPL5
  • Tautomer


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