A central problem in computational biophysics is the treatment of titratable residues in molecular dynamics simulations of large biological macromolecular systems. Conventional simulation methods ascribe a fixed ionization state to titratable residues in accordance with their pK _a and the pH of the system, assuming that an effective average model will be able to capture the predominant behavior of the system. While this assumption may be justifiable in many cases, it is certainly limited, and it is important to design alternative methodologies allowing a more realistic treatment. Constant-pH simulation methods provide powerful approaches to handle titratable residues more realistically by allowing the ionization state to vary statistically during the simulation. Extending the molecular mechanical (MM) potential energy function to a family of potential functions accounting for different ionization states, constant-pH simulations are designed to sample all accessible configurations and ionization states, properly weighted according to their Boltzmann factor. Because protonation and deprotonation events correspond to a change in the total charge, difficulties arise when the long-range Coulomb interaction is treated on the basis of an idealized infinite simulation model and periodic boundary conditions with particle-mesh Ewald lattice sums. Charging free-energy calculations performed under these conditions in aqueous solution depend on the Galvani potential of the bulk water phase. This has important implications for the equilibrium and nonequilibrium constant-pH simulation methods grounded in the relative free-energy difference corresponding to the protonated and unprotonated residues. Here, the effect of the Galvani potential is clarified, and a simple practical solution is introduced to address this issue in constant-pH simulations of the acid-sensing ion channel (ASIC).