If titratable sites are "chemically" or "topologically" coupled, the force field parameters of one site depend on the value of the λ coordinate of the other site, and vice versa. For example, histidine can exist in three protonation states, as shown in Figure . In most force fields, the partial charges of all atoms in the His side chain, including the two sites, depend on the protonation state. Hence, if the N δ site changes protonation, also the electrostatic interactions of the N site are affected.