SAMPL7 physical property prediction from EC-RISM theory

Inspired by the successful application of the embedded cluster reference interaction site model (EC-RISM), a combination of quantum–mechanical calculations with three-dimensional RISM theory to predict Gibbs energies of species in solution within the SAMPL6.1 (acidity constants, pK(a)) and SAMPL6.2 (octanol–water partition coefficients, log P) the methodology was applied to the recent SAMPL7 physical property challenge on aqueous pK(a) and octanol–water log P values. Not part of the challenge but provided by the organizers, we also computed distribution coefficients log D(7.4) from predicted pK(a) and log P data. While macroscopic pK(a) predictions compared very favorably with experimental data (root mean square error, RMSE 0.72 pK units), the performance of the log P model (RMSE 1.84) fell behind expectations from the SAMPL6.2 challenge, leading to reasonable log D(7.4) predictions (RMSE 1.69) from combining the independent calculations. In the post-submission phase, conformations generated by different methodology yielded results that did not significantly improve the original predictions. While overall satisfactory compared to previous log D challenges, the predicted data suggest that further effort is needed for optimizing the robustness of the partition coefficient model within EC-RISM calculations and for shaping the agreement between experimental conditions and the corresponding model description. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10822-021-00410-9.