An explicit-solvent hybrid QM and MM approach for predicting pKa of small molecules in SAMPL6 challenge

Abstract

In this work we have developed a hybrid QM and MM approach to predict pKa of small drug-like molecules in explicit solvent. The gas phase free energy of deprotonation is calculated using the M06-2X density functional theory level with Pople basis sets. The solvation free energy difference of the acid and its conjugate base is calculated at MD level using thermodynamic integration. We applied this method to the 24 drug-like molecules in the SAMPL6 blind pKa prediction challenge. We achieved an overall RMSE of 2.4 pKa units in our prediction. Our results show that further optimization of the protocol needs to be done before this method can be used as an alternative approach to the well established approaches of a full quantum level or empirical pKa prediction methods.

Keywords: Explicit solvent; Hybrid QM and MM; SAMPL6; pKa prediction.

Fig. 1

Molecules in the SAMPL6 prediction challenge.

Fig. 2

Thermodynamic cycles used in the pKa calculations a) chemical reaction of acid dissociation. This relates the free energy of dissociation in the aqueous phhase as with the gas phase free energy of dissociation and solvation free energies of the acid, base and proton. b) Alchemical cycle for deprotonation. This cycle relates the solavtion free energy difference of the HA and A⁻ with difference in free energy for deprotonation in the aqueous and gas phases.

Fig. 3

Workflow for the hybrid QM and MM pKa prediction approach.

Fig. 4

Plot of the closest analysis scheme and experimental pKa values. Plot courtesy of the organizers https://github.com/MobleyLab/SAMPL6/blob/master/physical_properties/pKa/analysis/analysis_of_typeI_predictions/analysis_outputs_closest/pKaCorrelationPlots/0wfzo.pdf