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Homology Model of the GABA_A Receptor Examined Using Brownian Dynamics

Megan O'Mara ^*, Brett Cromer , Michael Parker  and Shin-Ho Chung ^*

^* Department of Theoretical Physics, Research School of Physical Sciences, Australian National University, Canberra, Australia; and Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, University of Melbourne, Melbourne, Australia

Correspondence: Address reprint requests to Shin-Ho Chung, Fax: 61-2-6247-2792; E-mail: shin-ho.chung{at}anu.edu.au.

We have developed a homology model of the GABA_A receptor, using the subunit combination of 1ß22, the most prevalent type in the mammalian brain. The model is produced in two parts: the membrane-embedded channel domain and the extracellular N-terminal domain. The pentameric transmembrane domain model is built by modeling each subunit by homology with the equivalent subunit of the heteropentameric acetylcholine receptor transmembrane domain. This segment is then joined with the extracellular domain built by homology with the acetylcholine binding protein. The all-atom model forms a wide extracellular vestibule that is connected to an oval chamber near the external surface of the membrane. A narrow, cylindrical transmembrane channel links the outer segment of the pore to a shallow intracellular vestibule. The physiological properties of the model so constructed are examined using electrostatic calculations and Brownian dynamics simulations. A deep energy well of 80 kT accommodates three Cl^– ions in the narrow transmembrane channel and seven Cl^– ions in the external vestibule. Inward permeation takes place when one of the ions queued in the external vestibule enters the narrow segment and ejects the innermost ion. The model, when incorporated into Brownian dynamics, reproduces key experimental features, such as the single-channel current-voltage-concentration profiles. Finally, we simulate the 2 K289M epilepsy inducing mutation and examine Cl^– ion permeation through the mutant receptor.

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