LAUSR

The aid of monoamine transporter (MAT) proteins in terminating the effect of neurotransmitters in the synaptic cleft is crucial for the maintenance of proper neurotransmitter concentrations. Termination of effect is achieved via the process of reuptake, where the proteins bind neurotransmitters to a central substrate binding site and transport the substrate to the other side of the membrane through a permeation pathway. The MAT family of proteins includes the serotonin transporter (SERT), which is responsible for the reuptake of serotonin from the synaptic cleft. SERT, as well as the other MAT proteins are implicated in several psychological disorders, including depression, anxiety, and addiction. Treatments for these disorders are focused on the inhibition of the MAT system, especially SERT. These drugs are known as selective serotonin reuptake inhibitors, which act by binding to the substrate site of SERT, preventing the reuptake of serotonin. Recent work in our lab has focused on identifying the complete transport mechanism of SERT computationally, employing both a single bilayer and dual bilayer system to investigate this phenomenon. The work presented here represents the data collected from our most recent dual bilayer system. Herein we utilized the newly crystallized human SERT protein (PDB 5I6X), embedded in POPE lipid membranes. The dual bilayer setup allows the system to maintain ion concentrations on either side of the membrane when periodic boundary conditions are implemented. Ions were added to either side of the membrane at physiological concentrations, keeping the membrane potential at around −70mV, representative of resting potential. Understanding more fully the complete transport process, with specific attention paid to the reset mechanism, can aid in drug discovery and design for treatments that better alleviate symptoms of depression and related disorders. Presented here are the molecular dynamics and conformational data from our ongoing simulations of the dual bilayer SERT system.