Molecular Dynamics of Mood: Unveiling the Mental Health Link through Serotonin Transporter Conformational Changes
Yanmin LiAbstract
Objective
This study employs molecular dynamics (MD) simulations to investigate the conformational dynamics of the serotonin transporter (SERT), aiming to elucidate the atomic-level mechanisms that link its structural changes to serotonin reuptake regulation—a core process influencing psychological states and mental health.
Subjects and Methods
To investigate the molecular underpinnings of mood and anxiety disorders, all-atom MD simulations of the human serotonin transporter (SERT) were conducted. Multiple 500-ns simulations captured its conformational cycle. The free energy landscape and critical states were analyzed with a Markov State Model, and in silico mutagenesis probed residues whose dysfunction is implicated in emotional dysregulation.
Results
The simulations identified a multi-step conformational pathway, revealing a metastable occluded state as a major kinetic bottleneck controlled by specific salt-bridge interactions. Perturbing this state through computational mutation significantly altered the predicted transport cycle. Furthermore, simulations within a modeled lipid raft environment showed that membrane composition can modulate SERT dynamics, suggesting a biophysical link to potential dysregulation in mood disorders.
Conclusions
This work provides a dynamic, atomic-resolution perspective on how SERT conformational shifts mechanistically regulate serotonin reuptake. The identified critical states and gating mechanisms offer novel structural targets for developing next-generation therapeutics aimed at mood and anxiety disorders by targeting functional dynamics rather than static structures.
Acknowledgements
This work was supported by the Liaoning Provincial Science and Technology Joint Fund (2023-BSBA-171); PhD Research Initiation Fund Project of Liaodong University (2024BS012).
Corresponding Author
Yanmin Li, Liaodong University, Dandong 130000, Liaoning, China.