  Proteins change their charge state through protonation and redox reactions as
well as through binding charged ligands. The free energy of these reactions are
dominated by solvation and electrostatic energies and modulated by protein
conformational relaxation in response to the ionization state changes. Although
computational methods for calculating these interactions can provide very
powerful tools for predicting protein charge states, they include several
critical approximations of which users should be aware. This chapter discusses
the strengths, weaknesses, and approximations of popular computational methods
for predicting charge states and understanding their underlying electrostatic
interactions. The goal of this chapter is to inform users about applications
and potential caveats of these methods as well as outline directions for future
theoretical and computational research.
