An Electrostatic Funnel in the GABA-Binding Pathway

Timothy S Carpenter and Felice C Lightstone

PLOS Computational Biology, 2016, vol. 12, issue 4, 1-23

Abstract: The γ-aminobutyric acid type A receptor (GABAA-R) is a major inhibitory neuroreceptor that is activated by the binding of GABA. The structure of the GABAA-R is well characterized, and many of the binding site residues have been identified. However, most of these residues are obscured behind the C-loop that acts as a cover to the binding site. Thus, the mechanism by which the GABA molecule recognizes the binding site, and the pathway it takes to enter the binding site are both unclear. Through the completion and detailed analysis of 100 short, unbiased, independent molecular dynamics simulations, we have investigated this phenomenon of GABA entering the binding site. In each system, GABA was placed quasi-randomly near the binding site of a GABAA-R homology model, and atomistic simulations were carried out to observe the behavior of the GABA molecules. GABA fully entered the binding site in 19 of the 100 simulations. The pathway taken by these molecules was consistent and non-random; the GABA molecules approach the binding site from below, before passing up behind the C-loop and into the binding site. This binding pathway is driven by long-range electrostatic interactions, whereby the electrostatic field acts as a ‘funnel’ that sweeps the GABA molecules towards the binding site, at which point more specific atomic interactions take over. These findings define a nuanced mechanism whereby the GABAA-R uses the general zwitterionic features of the GABA molecule to identify a potential ligand some 2 nm away from the binding site.Author Summary: Neurotransmitters convey signals from one neuron to the next and are indispensable to the functioning of the nervous system. These small molecules bind to receptors to exert their action. One of the most important neurotransmitters is γ-aminobutyric acid (GABA), which binds to its type A receptor to exert an inhibitory influence on the neuron. Many drugs, both medicinal and nefarious, bind to these neuroreceptors and alter the balance of neuronal signals in the brain. There is a fine balance between these drugs eliciting the desired effect, and causing unwanted and sometimes irreversible alterations in neural behavior. To study this critical binding event, we are using computational simulations to observe precisely how the GABA molecule binds to its type A receptor (GABAA-receptor). One hundred individual simulations were carried out where GABA was placed near the binding site and then allowed to freely bind to the GABAA-receptor. Binding occurred in 19 of these simulations. Statistical analysis of these binding simulations reveals the consistent pathway taken by GABA molecules to enter the binding site. This improved understanding of the binding event enables development of safer medicinal neuroactive drugs and countermeasures for effects of neuronal chemical trauma.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1004831

DOI: 10.1371/journal.pcbi.1004831

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