Molecular Dynamics Reveals Structural Consequences of Schizophrenia-Associated SLC6A1 Variants

The SLC6A1 gene encodes the GAT-1 transporter, which mediates the reuptake of GABA in the central nervous system (CNS). Missense variants in this gene are associated with the development of neuropsychiatric disorders, including schizophrenia. Although in vitro assays demonstrate a loss of transport activity, they do not elucidate how specific amino acid substitutions disrupt local interactions within the protein. To delineate the structural consequences of these mutations, we analyzed the inward-open apo-state of human GAT-1 (PDB: 7Y7V) using microsecond-scale molecular dynamics (MD) simulations. This study compares the wild-type transporter with mutant forms, including the schizophrenia-associated variants R211C and A305T, alongside the A346S variant selected via deep learning-based pathogenicity predictors. The results demonstrate that these mutations do not globally destabilize the protein structure; rather, they induce specific rearrangements within local contact networks. The R211C substitution abolishes a hydrogen bond at the interface of extracellular loop 2 (EL2) and transmembrane helix 4 (TM4). A305T alters the TM1–TM6 interface adjacent to the sodium ion-binding site, and A346S strengthens TM1/TM6–EL4 interactions. The identified structural shifts suggest how pathogenic mutations remodel the GAT-1 interaction network and alter its conformational dynamics. These findings provide a foundation for subsequent molecular docking aimed at drug repurposing and for comprehensive MD modeling of the complete GAT-1 transport cycle.