The correction potentials for the solvent density (Eq. ( )) and orientation (Eq. ( )) were built up simultaneously over a LE phase of 20 ns. For the density bias, the force constant was set to b ρ = 10 -2 kJ mol -1 and the kernel width ω ρ in grid units to 1. The orientational bias relied on b µ = 10 -5 kJ mol -1 and ω µ = 2. In slab geometry, the number of grid points was set to K = 51 (∆ = 0.1 nm). In spherical geometry it was set to K = 73 (∆ = 0.096 nm). The build-up was carried out separately for each distinct cutoff. In spherical geometry, it was carried out without the aforementioned position restraint on the central water molecule. The correction potentials used in the US phase were defined as averages over the last 15 ns of the LE phase, and the production runs of the US phase were carried out for 10 ns.