) converges when 𝐺 𝑐𝑝 (𝑅 R is large enough such that the presence of the solute does not affect the distribution of the solvent molecules. The reference state configurations are generated by the ComplexMixtures.jl package for each frame, by computing random positions for solvent molecules with conformations sampled from the bulk phase of the simulation, with a density corresponding to the bulk density. The minimum-distance count is, then, repeated for these reference configurations. Formal details of the procedure are described in previous publications . Each system's effective concentration was recalculated from the NPT production runs using the bulk region of the simulation box .