Thermodynamical Origin of Nonmonotonic Inserting Behavior of Imidazole Ionic Liquids into the Lipid Bilayer

The GPU-accelerated molecular dynamics simulations are performed to explore the dynamical inserting process of ionic liquids (ILs) into the lipid bilayer. We found that the free ions and clusters coexist in the system, but only the cation can insert into the lipid bilayer. In specific, after a microsecond-scale simulation (up to 1.16 μs), the inserting rate increases first and then decreases nonmonotonic as side chain of cation (n_chain) elongates, peaking at n_chain = 10. However, the inserting free energy decreases with n_chain, indicating the inserting process is easier for the larger n_chain. Such contrary originates from the formation of cluster, where the cluster dissociating energy shows that only cluster for n_chain ≤ 10 can dissociate spontaneously. Hence, the inserting rate is determined by the balance between n_chain and cluster stability. These quantitative competition mechanisms shed light to the rational design of the biocompatible ILs toward their applications in the biochemical-related fields.