Molecular Dynamics Simulations of GABA Binding to the GABA(C) Receptor: The Role of Arg(104)

GABA is the major inhibitory neurotransmitter in the nervous system and acts at a variety of receptors including GABA(C) receptors, which are a subclass of GABA(A) receptors. Here we have used molecular dynamics simulations of GABA docked into the extracellular domain of the GABA(C) receptor to explain the molecular interactions of the neurotransmitter with the residues that contribute to the binding site; in particular, we have explored the interaction of GABA with Arg(104). The simulations suggest that the amine group of GABA forms cation-π interactions with Tyr(102) and Tyr(198), and hydrogen-bonds with Gln(83), Glu(220), Ser(243), and Ser(168), and, most prominently, with Arg(104). Substituting Arg(104) with Ala, Glu, or Lys, which experimentally disrupt GABA(C) receptor function, and repeating the simulation revealed fewer and different bonding patterns with GABA, or the rapid exit of GABA from the binding pocket. The simulations therefore unveil interactions of GABA within the binding pocket, and explain experimental data, which indicate that Arg(104) is critical for the efficient functioning of the receptor.