Molecular dynamics methods of calculating pK values make it possible to include full flexibility of the titrated molecule.
Molecular dynamics based methods are typically much more computationally expensive, and not necessarily more accurate, ways to predict pK values than approaches based on the Poisson–Boltzmann equation. Limited conformational flexibility can also be realized within a continuum electrostatics approach, e.g., for considering multiple amino acid sidechain rotamers. In addition, current commonly used molecular force fields do not take electronic polarizability into account, which could be an important property in determining protonation energies.