Includes MD simulation data on water density profiles and maps. (A) Water density profiles computed using gmx density. The solid line is computed from an all-atom MD simulation with SPC embedded in a POPC bilayer. The faded lines correspond to water densities extracted from five independent 20 μs MD simulations of SPC embedded in a model endoplasmic reticulum membrane. (B) Snapshot illustrating water penetration inside the SPC window without the formation of a water pore. (C) Snapshot showcasing a degree of lipid flip-flop across the ER membrane model.