COSMO-RS blind prediction of distribution coefficients and aqueous pKa values from the SAMPL8 challenge

Abstract

The SAMPL8 blind prediction challenge, which addresses the acid/base dissociation constants (pKa) and the distribution coefficients (logD), was addressed by the Conductor like Screening Model for Realistic Solvation (COSMO-RS). Using the COSMOtherm implementation of COSMO-RS together with a rigorous conformational sampling, yielded logD predictions with a root mean square deviation (RMSD) of 1.36 log units over all 11 compounds and seven bi-phasic systems of the data set, which was the most accurate of all contest submissions (logD).

For the SAMPL8 pKa competition, participants were asked to report the standard state free energies of all microstates, which were then used to calculate the macroscopic pKa. We have used COSMO-RS based linear free energy fit models to calculate the requested energies. The assignment of the calculated and experimental pKa values was made on the basis of the popular transitions, i.e. the transition hat was predicted by the majority of the submissions. With this assignment and a model that covers both, pKa and base pKa, we achieved an RMSD of 3.44 log units (18 pKa values of 14 molecules), which is the second place of the six ranked submissions. By changing to an assignment that is based on the experimental transition curves, the RMSD reduces to 1.65. In addition to the ranked contribution, we submitted two more data sets, one for the standard pKa model and one or the standard base pKa model of COSMOtherm. Using the experiment based assignment with the predictions of the two sets we received a RMSD of 1.42 log units (25 pKa values of 20 molecules). The deviation mainly arises from a single outlier compound, the omission of which leads to an RMSD of 0.89 log units.