Designing Reaction Coordinate for Ion-Induced Pore-Assisted Mechanism of Halide Ions Permeation through Lipid Bilayer by Umbrella Sampling

Ion permeation mechanism through lipid membranes helps to understand cellular processes. We propose new reaction coordinates that allow ions to permeate according to their water affinity and interaction with the hydrophilic layer. Simulations were done for three different halides (F^–, Cl^–, and I^–) in two different lipid bilayers, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dinervonoyl-sn-glycero-3-phosphocholine (DNPC). It is found that the involvement of the water molecules decreases the free energy barrier. The ions were found to follow different pathways for permeation. Formation of proper pores required a collaboration effort of the hydration shell water molecules and the hydrophilic lipid layer, which was favored in the case of Cl^– ions. The optimum charge density and good water affinity of Cl^– with respect to F^– and I^– ions helped to form the pore. The effect was prominently seen in the case of DNPC membrane because of its higher hydrophobic thickness. The umbrella sampling results were compared with other methods such as the Markov state model (MSM) and well-tempered metadynamics (WT-metaD).