pKa is one essential molecular property to characterize proton-coupled electron transfer process. However, accurate pKa computations for molecules are still challenging in computational chemistry. Here, based on the Linear Combination of Atomic Potential (LCAP) approach to describe alchemical transformations, we developed a new approach, named fractional number of proton (FNP), to compute pKa values robustly. Similar to fractional number of electron (FNE) method for redox potential, the proton in FNP disappears gradually. We also showed that FNE and FNP are two special cases of LCAP. Two computational strategies (with/without bond restraints between the proton and the solute molecule) were explored to apply FNP with QM/MM simulations for several small molecules in aqueous solution. Our results demonstrate that FNP is a simple and efficient method to compute pKa. To further improve the accuracy of FNP in QM/MM simulations, accurate descriptions between the QM and MM subsystems including electrostatic and van der Waals interactions need to be developed in future works.

Computing pK<sub>a</sub> values using fractional number of proton approach

243rd National Meeting (2012)

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Computing pKa values using fractional number of proton approach

Computing pK_a values using fractional number of proton approach