Free energy profile of the substrate-induced occlusion of the human serotonin transporter.
Markov state model
free energy
occlusion
serotonin transporter
time-lagged independent component analysis
transport cycle
Journal
Journal of neurochemistry
ISSN: 1471-4159
Titre abrégé: J Neurochem
Pays: England
ID NLM: 2985190R
Informations de publication
Date de publication:
05 Feb 2024
05 Feb 2024
Historique:
revised:
05
12
2023
received:
06
10
2023
accepted:
15
01
2024
medline:
6
2
2024
pubmed:
6
2
2024
entrez:
5
2
2024
Statut:
aheadofprint
Résumé
The 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 energetically downhill for the 5HT-bound transporter. Force distribution analyses show that the interactions of 5HT with the bundle domain are crucial. During occlusion, attractive forces steadily increase and pull on the bundle domain, which leads to SERT occlusion. Some interactions become repulsive upon full occlusion, suggesting that SERT creates pressure on 5HT to promote its movement towards the cytosol.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Austrian Science Fund
ID : P32017
Organisme : Austrian Science Fund
ID : P34670
Organisme : HORIZON EUROPE Marie Sklodowska-Curie Actions
ID : 860954
Informations de copyright
© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
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