Water Molecule(s) Inside the Selectivity Filter of Aquaporin 1: A DFT Study.

Aquaporin 1 (AQP1) is a transmembrane protein that acts as a highly selective channel for the rapid passage of water across cell membranes, driven by osmotic gradients. The narrowest part of the water channel pore-the selectivity filter (SF)-plays a key role in ensuring selective and efficient water transport. In this study, density functional theory (DFT) at the M062X/6-311+G(d,p) level was used to identify the preferred position of the water molecule(s) inside the SF and to elucidate the forces that lead to its displacement during permeation. A systematic scan along the pore axis identified a well-defined energy minimum where a single water molecule was optimally stabilized by hydrogen bonds with SF residues. A second water molecule was introduced to study how the incoming water affects the translocation of the first water molecule. The resulting energy and force profiles reveal that the approaching water molecule gradually pushes the bound water forward, ultimately occupying its favorable binding site. These results provide an atomistic description of the positioning and displacement of water molecules in SF and offer a quantitative view of the fundamental interactions that govern water transport in AQPs.