Fluorescence microscopy imaging and molecular dynamics simulation studies on methylamphetamine solvation fluctuation...

Methylamphetamine (METH) is a smaller neuronal stimulant molecule with a distinctive dipolar nature. This specific chemical structure enables it to interact and partition into both the hydrophobic and hydrophilic domains of the lipid bilayer through a process facilitated by its solvation thermodynamics in the surrounding environment of the cell membranes. Disruption of the lipid integrity at the molecular level arises from complex solvation dynamics of small drugs and alterations in the bilayer organization, which remain incompletely understood. These could be the likely underlying mechanism for METH's permeating easily while clustering near headgroup levels inside the bilayer, interfering with the normal neuronal functions, such as forced release of neurotransmitters into the synaptic cleft and their abnormal accumulation in brain tissues. By integrating the fluorescence imaging assay techniques to detect the real time ion permeability and diffusion changes of the membrane with molecular dynamics simulations, we revealed that METH permeates readily and partitions preferentially into the lipid bilayer compared to the extracellular water level near the lipid bilayer headgroup interface, driving aggregations and assembling, causing disruptions that enhance the membrane fluidity and ion permeability, including increased calcium flux across lipid vesicles. These results provide a molecular-level insight into the mechanisms by which METH alters solvation dynamics and bilayer structure, highlighting how small amphipathic drugs compromise the membrane integrity and neuronal function, offering a framework for studying drug-induced perturbations of cell membrane integrity.