Deciphering Aquaporin-1 Permeability Modulation by Membrane Lipid Composition and Bilayer Mechanical Stress via Atomistic Simulations

Abstract

Aquaporin-1 (AQP1) is a critical water channel whose functionality is inherently tied to its surrounding lipid environment. Using atomistic molecular dynamics (MD) simulations totaling several microseconds, we investigated the coupled influence of membrane composition and bilayer mechanical tension on AQP1 water permeability. Specifically, systems featuring varying concentrations of anionic lipids (e.g., POPG, Cardiolipin) and differential lateral pressures were analyzed. Our results reveal a non-linear modulation of water flux, quantified via single-channel permeability coefficients and potential of mean force (PMF) profiles, across the channel's selectivity filter. High mechanical tension, regardless of the lipid type, consistently induced a statistically significant decrease in water conductance, attributed to a subtle yet critical tilting of the pore-lining helices and a local increase in the energy barrier within the NPS region. Conversely, specific anionic lipid compositions attenuated this effect, suggesting a compensatory, charge-mediated stabilization of the channel structure under stress. These findings underscore the necessity of considering the membrane's chemomechanical state when modeling AQP1 function and provide essential insights for rational drug design targeting the ADMET properties of water-soluble compounds.