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Article

Barriers to Ion Translocation in Cationic and Anionic Receptors from the Cys-Loop Family

Supporting Info

Ivaylo Ivanov,*^†^‡ Xiaolin Cheng,^†^§ Steven M. Sine,^# and J. Andrew McCammon^†^‡^§

Contribution from the Department of Chemistry and Biochemistry, Department of Pharmacology, Howard Hughes Medical Institute, and Center for Theoretical Biological Physics, University of CaliforniaSan Diego, 9500 Gilman Drive, La Jolla, California 92093-0365, and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

J. Am. Chem. Soc., 2007, 129 (26), pp 8217–8224

DOI: 10.1021/ja070778l

Publication Date (Web): June 7, 2007

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

†

Department of Chemistry and Biochemistry, University of CaliforniaSan Diego.

‡

Department of Pharmacology, University of CaliforniaSan Diego.

Center for Theoretical Biological Physics, University of CaliforniaSan Diego.

Howard Hughes Medical Institute, University of CaliforniaSan Diego.

Mayo Clinic College of Medicine.

, iivanov@mccammon.ucsd.edu

Abstract

Understanding the mechanisms of gating and ion permeation in biological channels and receptors has been a long-standing challenge in biophysics. Recent advances in structural biology have revealed the architecture of a number of transmembrane channels and allowed detailed, molecular-level insight into these systems. Herein, we have examined the barriers to ion conductance and origins of ion selectivity in models of the cationic human α7 nicotinic acetylcholine receptor (nAChR) and the anionic α1 glycine receptor (GlyR), based on the structure of Torpedo nAChR. Molecular dynamics simulations were used to determine water density profiles along the channel length, and they established that both receptor pores were fully hydrated. The very low water density in the middle of the nAChR pore indicated the existence of a hydrophobic constriction. By contrast, the pore of GlyR was lined with hydrophilic residues and remained well-hydrated throughout. Adaptive biasing force simulations allowed us to reconstruct potentials of mean force (PMFs) for chloride and sodium ions in the two receptors. For the nicotinic receptor we observed barriers to ion translocation associated with rings of hydrophobic residuesVal13‘ and Leu9‘in the middle of the transmembrane domain. This finding further substantiates the hydrophobic gating hypothesis for nAChR. The PMF revealed no significant hydrophobic barrier for chloride translocation in GlyR. For both receptors nonpermeant ions displayed considerable barriers. Thus, the overall electrostatics and the presence of rings of charged residues at the entrance and exit of the channels were sufficient to explain the experimentally observed anion and cation selectivity.

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