Computational methods typically designate tautomeric states ("microstates") for acid and base forms of a compound separated by a unit charge upon (de-)protonation. Their free energies can be linked individually in a pair-wise manner ("microstate transitions") to yield so-called microstate pK a values from which the macroscopic pK a can be determined . Alternatively, the tautomer free energies, combined across the underlying conformational states, contribute to the ratio of partition functions representing acid and base forms, allowing the direct calculation of macroscopic acidity constants . A complication arises if, as is common practice with quantum-mechanical approaches, the difference of solution-state (standard) free energies for differently charged species, (A - aq ) and (HA aq ) for a general reaction