Figure shows that relative performance of constant pH simulations with charge interpolation does not decrease when the number of titratable sites included in the simulation increases. Most of the 30-40% drop in performance compared to a normal MD simulation with the same version of GROMACS is caused by the additional calculations and reductions in the non-bonded pair-interaction kernels that are required to obtain the real-space part of the electrostatic potential (Φ(R i , λ) in Equation ).