The crystal structures are usually resolved in cryogenic temperatures. It was recently demonstrated that water networks may enclose different water conformation preference in room temperature (or in the physiological temperature) than in those cryogenic conditions . The crystal structure data related to water should always be interpreted with some caution considering these findings. The high-energy of the conserved water with SII-P binder in this KRAS conformation, may offer a partial explanation the observed high fluctuation of the switch-II in microsecond timescale molecular dynamics simulations as observed with the inhibitors here and earlier with sotorasib . Our results suggest that the inhibitors display discrepancy in their impact on the conserved water behavior and its interactions with KRAS. Among the studied inhibitors JDQ443 and AZD4625 appeared the most repulsive for the conserved water, while