What Are the Essential Water Molecules in Regulating Lipid Membrane Fluidity?

Living organisms often endure extreme dehydration, which disrupts the cell membrane structure and function. Dehydration can induce a fluid-to-gel phase transition in lipid bilayers, compromising their fluidity and biological role. Lipid bilayer self-assembly is governed by intricate interactions between water and lipid head groups, but which water molecules are crucial for maintaining fluidity? We address this fundamental question using molecular dynamics (MD) simulations of a liquid-ordered (Lo) lipid bilayer over a hydration range of h = 2-30. We have identified a critical threshold at hydration level h = 9, below which dehydration severely impacts lipid packing and dynamics. Water molecules hydrogen-bonded to the lipid head groups, particularly phosphate groups, play a dominant role in preserving fluidity. When outer hydration shells are lost, hydrogen bonds between lipids and water overwhelmingly strengthen, likely reducing membrane fluidity. These insights enhance our understanding of local dehydration processes, such as cell-cell fusion, and the survival mechanisms of anhydrobiotic organisms and extremophiles.