Direct theoretical methods are advantageous for the prediction of pKa, as relative methods rely upon the experimental values of reference acid molecules that can limit application of the method to well-characterized systems. Here, a direct route is introduced, which incorporates the SMD universal solvation model1 within the correlation consistent Composite Approach (ccCA). This Solv-ccCA methodology has been used for the prediction of theoretical pKa values for nitrogen-containing species to within a mean absolute deviation (MAD) of 1.0 pKa unit from experimental values by utilizing a thermodynamic cycle that combines gas-phase and solution-phase calculations. Several density functionals, including B3LYP, B97-1, B97-2, B98, BMK, M06, and M06-2X, were also evaluated for use with SMD and for comparison to Solv-ccCA.

Utilizing the recently developed ONIOM-ccCA methodology, the proton affinities (PAs) of small biomolecules (∼15 nonhydrogen atoms) were determined. The ONIOM-ccCA method was used to predict the PAs of eight amine-containing molecules and these predictions were then compared with experiment. In these comparisons, a protocol for the determination of the model system size was established, and the low level method and basis set for the real system component of ONIOM-ccCA were considered. Several possible density functionals were investigated for description of the real system (low layer), including B3LYP, B97-1, B97-2, B98, BMK, M06, and M06-2X. The resulting proton affinities were compared both to experiment and to theoretical values that were calculated using the correlation consistent Composite Approach (ccCA). The impact of the choice of augmented correlation consistent basis sets in the ONIOM-ccCA low level calculation was also examined, and PAs calculated with augmented and non-augmented basis sets were compared to those extrapolated to the complete basis set (CBS) limit. ONIOM(ccCA:B3LYP/aug-cc-pVDZ) was then applied to deoxyribonucleosides to determine the PAs at possible sites of protonation.

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