For each AP, a pool of grid points is defined, containing the most favorable energy location at a distance between 2.5 and 3.6 Å from the AP and an angle ≤ 90 • from the AV. Thus, while energetically favorable APs will have higher chance to be filled first at the expenses of those with less or no favorable positions available, different placement orders can still be sampled during the simulation. Spherical water placement The initial location of each water is identified by placing a spherical water molecule (Fig. step 2), and calculating its energy according to the grid maps. The choice of the position of a spherical water molecule i is calculated using the energy of the grid points pool defined around each AP using the same geometric criteria as the placement order. The position is then picked based on Boltzmann probabilities p j in eq. 1 and accepted or rejected using equation 2.