COMPUTATIONAL INVESTIGATION ON SUBSTRATE UPTAKE AND RELEASE IN A GLUTAMATE TRANSPORTER

An unbalance in the glutamate concentration along the neuronal network can lead to an incorrect signal transduction and to severe neurodegenerative diseases such as Alzheimer’s or Parkinson’s. Glutamate transporters play a crucial role in this respect since they are responsible for the reuptake of the neurotransmitter from the synaptic cleft thus controlling the glutamate concentration. Understanding the molecular mechanism of this transporter can provide the possibility of an exogenous control. Structural studies have shown that this transporter can assume four conformations, thus suggesting a pronounced dynamical behavior. However, the last state leading to the substrate internalization have not been characterized and many aspects of the transporter mechanism still remain unclear. Using metadynamics simulations, we investigate the substrate uptake from the synaptic cleft and its release in the intracellular medium. In addition, we focus on the role of ions and substrate during these processes and on the stability of the different conformations assumed by the transporter.1 These dynamical results can complement the available X-ray data and provide a thorough description of the entire process of substrate uptake, internalization, and release.