Each multi-try MC step starts with the system in an initial state indexed as i = 0 and with energy 𝐸 0 . From this state, additional trial states i = 1…NMC are generated in which a water molecule, chosen with uniform probability from those within a region defined in the frame of reference of a residue, termed the MC region (Section 2.3), is moved to a sterically feasible location chosen with uniform probability within the same MC region. Thus, water moves can only occur within a single region, preserving detailed balance. Sterically feasible locations are identified via a steric grid within the MC region, as previously detailed. For each trial move, a fast but coarse approximation to the energy change, Δ𝐸 𝑖 𝑐𝑜𝑎𝑟𝑠𝑒 is then computed. If this energy difference is lower than a user-defined cutoff, i.e., Δ𝐸 𝑖 𝑐𝑜𝑎𝑟𝑠𝑒 < Δ𝐸 𝑐𝑢𝑡 then a full PME energy calculation is done to provide energy 𝐸 𝑖 . Otherwise, i.e., if Δ𝐸 𝑖 𝑐𝑜𝑎𝑟𝑠𝑒 > Δ𝐸 𝑐𝑢𝑡 , the energy of this trial state is treated as if it were infinite.