Free energy profile of the substrate ‐induced occlusion of the human serotonin transporter

We showed that the occlusion mechanism of the serotonin transporter (SERT) is an energetically downhill process which involves multiple intermediate conformations. We demonstrated that the transporter recognizes the presence of serotonin (5HT), which shifts the free energy equilibrium towards intermediate conformations that are stabilized by interactions between 5HT and conserved residues in TM1b and TM6a (D98 and F335). Increasing forces between 5HT and the bundle domain then pull SERT to fully occlude. This finding increases our understanding of the substrate recognition, the driving forces and the associated free energy changes. AbstractThe serotonin transporter (SERT) is a member of the Solute Carrier 6 (SLC6) family and is responsible for maintaining the appropriate level of serotonin in the brain. Dysfunction of SERT has been linked to several neuropsychiatric disorders, including depression, anxiety and obsessive-compulsive disorder. Therefore, an in-depth understanding of the mechanism on an atomistic level, coupled with a quantification of transporter dynamics and the associated free energies is required. Here, we constructed Markov state models (MSMs) from extensive unbiased molecular dynamics simulations to quantify the free energy profile of serotonin (5HT) triggered SERT occlusion and explored the driving forces of the mechanism of occlusion. Our results reveal that SERT occludes via multiple intermediate conformations and show that the motion of occlusion is ene...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research