Because changing the charge of a buffer particle in solution induces local rearrangements of the hydrogen bonding network that in turn could affect the proton affinity of a nearby titratable group, we want to minimize the impact of charging the buffer particles. To determine the charge range in which the buffers do not cause significant hydrogen bond network rearrangement, we ran AWH simulations with two ions, the charges of which are changed simultaneously in opposite directions (BUF 2 system). From the friction metric available in the AWH method, we estimated the local diffusion coefficient, which is related to the efficiency of sampling: The higher the friction, the slower the dynamics, and the more sampling is required to reach convergence. We calculated the friction coefficient (Figure ) for the coordinate associated with changing the charge on the buffer. For charges higher than 0.5 e the friction was more than 50% higher than for zero charges, reflecting longer correlation times and hence slower dynamics. We, therefore, conclude that the optimal range for the buffer charge is between -0.5 e and 0.5 e.