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).

脂质膜中离子渗透机制有助于理解细胞过程。本研究提出了新的反应坐标，该坐标允许离子根据其水亲和力及其与亲水层的相互作用进行渗透。针对三种不同的卤化物（F–、Cl–和I–）在两种不同的脂质双分子层中进行模拟，包括1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱（DPPC）和1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱（DNPC）。研究发现，水分子的参与降低了自由能垒。离子被发现遵循不同的渗透路径。适当孔隙的形成需要水化壳水分子与亲水脂质层的协作努力，这在Cl–离子的情况下尤为明显。与F–和I–离子相比，Cl–离子的最佳电荷密度和良好的水亲和力有助于孔隙的形成。这一效应在DNPC膜中尤为显著，因其具有更高的疏水厚度。伞采样结果与其他方法如马尔可夫状态模型（MSM）和温和调温元动力学（WT-metaD）进行了比较。