Title:Computational Insights into the Structure and Dynamics of the Human Serotonin Transporter N-Terminus by Microsecond Molecular Dynamics
Volume: 18
Issue: 3
Author(s): Sorin Draga*, Laura Olariu and Speranta Avram
Affiliation:
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest,Romania
Keywords:
Serotonin transporter, SERT, IDP, N-terminus, molecular dynamics, ab initio, PTMs.
Abstract:
Background: The human serotonin transporter is an important drug target for the treatment
of various medical conditions of which depression is the most important, but also include attention
deficit hyperactivity disorder, schizophrenia, social anxiety disorder and irritable bowel syndrome,
among others. The transmembrane portion of the human transporter has been studied extensively
and was first crystalized in 2016. However, the dynamical nature of the N-terminal segment
of protein and its post-translational modifications remain insufficiently explored.
Objective: The present study aims to evaluate the structure and dynamics of the N-terminal segment
of the human serotonin transporter and the presence and stability of possible secondary structure
elements along with its post-translational modifications and disorder propensity.
Methods: The segment was investigated using a combination of bioinformatics tools for physicochemical
characterization, secondary structure prediction, post-translational modifications and disorder
prediction, followed by ab initio modeling and microsecond long explicit solvent molecular
dynamics.
Results: Our study reveals the presence of metastable secondary structure elements, namely two alpha
helices and a beta-sheet, throughout the molecular dynamics run and identifies numerous sites
with high probability for post-translational modifications.
Conclusion: Our results show that, despite the intrinsically unstructured nature, the N-terminus
adopts a stable conformation with stable secondary structure elements, that could indicate an important
functional role for the segment. Also, there is a high probability that the segment undergoes
multiple post-translational modifications.