Molecular Dynamics of the Mutant GABA Transporter GAT-1: contribution to the Pathogenesis of Schizophrenia

Background. It is well established that the GABAergic system, which plays a crucial role in both activating and inhibiting neuronal communication, is involved in the pathogenesis of schizophrenia. Mutations in the structure of GABA transporters may represent a key process in the development of this disorder. Consequently, developing in silico models of protein transporter dynamics in the central nervous system could help elucidate their functional significance in the progression of the disease.

Aim: to model the structure and dynamics of the GAT-1 transporter within the neuronal membrane, taking into account the known schizophrenia-associated mutations, in order to refine our understanding of their functional relevance.

Methods. The molecular dynamics of both mutant and wild-type GABA transporter GAT-1 was simulated using GROMACS. The structures were based on PDB (7Y7V), with three missense substitutions (A93T, R211C, W495L) introduced in PyMOL. A membrane system was constructed via CHARMM-GUI, followed by solvation and ionization. Energy minimization was carried out, and the system was subsequently simulated under isobaric-isothermal conditions (T = 300 K) using the Parrinello-Rahman barostat. Dynamics were analyzed through RMSD, RMSF, and radius of gyration (Rg).

Results. Molecular dynamics simulations (100 ns) revealed that mutations in SLC6A1 lead to significant disruptions in both global and local stability of the GABA transporter. RMSD and RMSF analyses showed delayed stabilization of the mutant protein, increased fluctuations in key ion transport regions, and a potential loss of transport function. A slight increase in Rg in the mutant suggests preserved packing density but impaired binding capacity.

Conclusion. These alterations may negatively impact GABA reuptake, which is associated with cognitive impairments and schizophrenia symptoms, highlighting the need for further investigation into the structure and function of the transporter in the pathogenesis of neuropsychiatric disorders.

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