The model we presented here makes several simplifying assumptions, such as linearization of both the electrostatic and charge regulation contributions to the free energy as well as treating the proteins as spherical objects. With this, we also assume that any conformational changes do not contribute in a major fashion, which should be a valid approximation for proteins, unlike, for instance, in the case of polyelectrolyte chains or protein-RNA complexation . Nonetheless, this effect should be investigated further also in proteins, and recent advances in Monte Carlo and molecular dynamics simulations that include efficient computations of charge regulation effects should be of great aid in this . Constant-pH molecular dynamics simulations of protein protonisation behaviour would also allow to explore the question of protein protonisation fluctuations fully at the appropriate level without any linearization assumptions while providing a good comparison for the predictions of our model.