We performed the reference simulations as follows: The partial charges in the tripeptide systems were linearly interpolated between λ = -0.1 and λ = 1.1 with a step of 0.05. For His, all three λ-coordinates were changed under the constraint λ 1 + λ 2 + λ 3 = 1. For each set of λ values, called a grid point, we performed an 11 ns MD simulation, in which the ∂V /∂λ j were saved every ps and accumulated. The total charge of the system was kept neutral by simultaneously changing the charge of a single buffer particle. The fitting procedure is described in full detail in the accompanying paper. 15