Exploring gas permeability of cellular membranes and membrane channels with molecular dynamics

Aquaporins are a family of membrane proteins specialized in rapid water conduction across biological membranes. Whether these channels also conduct gas molecules and the physiological significance of this potential function have not been well understood. Here we report 140 ns of molecular dynamics simulations of membrane-embedded AQP1 and of a pure POPE bilayer addressing these questions. The permeability of AQP1 to two types of gas molecules, O2 and CO2, was investigated using two complementary methods, namely, explicit gas diffusion simulation and implicit ligand sampling. The simulations show that the central (tetrameric) pore of AQP1 can be readily used by either gas molecule to permeate the channel. The two approaches produced similar free energy profiles associated with gas permeation through the central pore: a -0.4 to -1.7 kcal/mol energy well in the middle, and a 3.6-4.6 kcal/mol energy barrier in the periplasmic vestibule. The barrier appears to be mainly due to a dense cluster of water molecules anchored in the periplasmic mouth of the central pore by four aspartate residues. Water pores show a very low permeability to O2, but may contribute to the overall permeation of CO2 due to its more hydrophilic nature. Although the central pore of AQP1 is found to be gas permeable, the pure POPE bilayer provides a much larger cross-sectional area, thus exhibiting a much lower free energy barrier for CO2 and O2 permeation. As such, gas conduction through AQP1 may only be physiologically relevant either in membranes of low gas permeability, or in cells where a major fraction of the cellular membrane is occupied by AQPs.