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Title: An Electrostatic Funnel in the GABA-Binding Pathway

Abstract

The γ-aminobutyric acid type A receptor (GABA A-R) is a major inhibitory neuroreceptor that is activated by the binding of GABA. The structure of the GABA A-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 GABA A-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’ thatmore » 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 GABA A-R uses the general zwitterionic features of the GABA molecule to identify a potential ligand some 2 nm away from the binding site.« less

Authors:
ORCiD logo [1];  [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division. Physical and Life Sciences Directorate
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE; LLNL Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1524718
Report Number(s):
LLNL-JRNL-674894
Journal ID: ISSN 1553-7358; 797862
Grant/Contract Number:  
AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 12; Journal Issue: 4; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 97 MATHEMATICS AND COMPUTING

Citation Formats

Carpenter, Timothy S., and Lightstone, Felice C. An Electrostatic Funnel in the GABA-Binding Pathway. United States: N. p., 2016. Web. doi:10.1371/journal.pcbi.1004831.
Carpenter, Timothy S., & Lightstone, Felice C. An Electrostatic Funnel in the GABA-Binding Pathway. United States. doi:10.1371/journal.pcbi.1004831.
Carpenter, Timothy S., and Lightstone, Felice C. Wed . "An Electrostatic Funnel in the GABA-Binding Pathway". United States. doi:10.1371/journal.pcbi.1004831. https://www.osti.gov/servlets/purl/1524718.
@article{osti_1524718,
title = {An Electrostatic Funnel in the GABA-Binding Pathway},
author = {Carpenter, Timothy S. and Lightstone, Felice C.},
abstractNote = {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.},
doi = {10.1371/journal.pcbi.1004831},
journal = {PLoS Computational Biology (Online)},
number = 4,
volume = 12,
place = {United States},
year = {2016},
month = {4}
}

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