Molecular Dynamics\nSimulation on the Conformational\nChange of a pH-Switchable Lipid

pH-sensitive\nlipids are important components of lipid nanoparticles,\nwhich enable the targeted delivery and controlled release of drugs.\nUnderstanding the mechanism of pH-triggered drug release at the molecular\nlevel is important for the rational design of ionizable lipids. Based\non a recently reported pH-switchable lipid, named SL2, molecular dynamics\n(MD) simulations were employed to explore the microscopic mechanism\nbehind the membrane destabilization induced by the conformational\nchange of pH-switchable lipids. The simulated results showed that,\nat neutral pH, the neutral SL2 lipids assembled with other components\n(helper lipids and cholesterol) to form a structurally ordered bilayer\nstructure. At this moment, the two hydrocarbon chains of SL2 were\nclosely aligned and inserted in an orderly manner inside of the membrane.\nWith a decrease in pH, the protonation of the pyridinium ring caused\na large degree of molecular structural change. The pyridinium ring\npreferred to form intramolecular H-bonds with the methoxy groups and\nintermolecular H-bonds with water, resulting in the flip of the pyridinium\nring. Meanwhile, due to the structural flip, the two alkane chains\nshowed a more open state, which perturbed the arrangement of molecules\nwithin the membrane. The perturbations caused local collapse of the\nmembrane and the formation of water molecule channels, which contributed\nto the pH-induced drug release. Our results verified the experimentally\nproposed mechanism at the molecular level and provided more complementary\ninformation, which are expected to have deeper insights into the pH-triggered\ndrug release.