Therapeutics designed to increase synaptic neurotransmitter levels by inhibiting neurotransmitter sodium symporters
(NSSs) classify a strategic approach to treat brain disorders such as depression or epilepsy, however, the critical
elementary steps that couple downhill flux of sodium to uphill transport of neurotransmitter are not distinguished as yet.
Here we present modelling of NSS member neuronal GAT1 with the substrate γ-aminobutyric acid (GABA), the major
inhibitory neurotransmitter. GABA binding is simulated with the occluded conformation of GAT1 homodimer in an explicit
lipid/water environment. Simulations performed in the 1-10 ns range of time elucidated persistent formation of halfextended
minor and H-bridged major GABA conformations, referred to as binding and traverse conformations, respectively.
The traverse GABA conformation was further stabilized by GAT1-bound Na+(1). We also observed Na+(1) translocation
to GAT1-bound Cl- as well as the appearance of water molecules at GABA and GAT1-bound Na+(2), conjecturing
causality. Scaling dynamics suggest that the traverse GABA conformation may be valid for developing substrate inhibitors
with high efficacy. The potential for this finding is significant with impact not only in pharmacology but wherever
understanding of the mechanism of neurotransmitter uptake is valuable.