Barriers to Ion Translocation in Cationic and Anionic Receptors from the Cys-Loop Family
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- 作者：Ivaylo Ivanov ; Xiaolin Cheng ; Steven M. Sine ; J. Andrew McCammon
- 刊名：Journal of the American Chemical Society
- 出版年：2007
- 出版时间：July 4, 2007
- 年：2007
- 卷：129
- 期：26
- 页码：8217 - 8224
- 全文大小：562K
- 年卷期：v.129,no.26(July 4, 2007)
- ISSN：1520-5126
文摘
Understanding the mechanisms of gating and ion permeation in biological channels and receptorshas been a long-standing challenge in biophysics. Recent advances in structural biology have revealedthe architecture of a number of transmembrane channels and allowed detailed, molecular-level insight intothese systems. Herein, we have examined the barriers to ion conductance and origins of ion selectivity inmodels of the cationic human 
7 nicotinic acetylcholine receptor (nAChR) and the anionic 1 glycine receptor(GlyR), based on the structure of Torpedo nAChR. Molecular dynamics simulations were used to determinewater density profiles along the channel length, and they established that both receptor pores were fullyhydrated. The very low water density in the middle of the nAChR pore indicated the existence of ahydrophobic constriction. By contrast, the pore of GlyR was lined with hydrophilic residues and remainedwell-hydrated throughout. Adaptive biasing force simulations allowed us to reconstruct potentials of meanforce (PMFs) for chloride and sodium ions in the two receptors. For the nicotinic receptor we observedbarriers to ion translocation associated with rings of hydrophobic residues-Val13' and Leu9'-in the middleof the transmembrane domain. This finding further substantiates the hydrophobic gating hypothesis fornAChR. The PMF revealed no significant hydrophobic barrier for chloride translocation in GlyR. For bothreceptors nonpermeant ions displayed considerable barriers. Thus, the overall electrostatics and thepresence of rings of charged residues at the entrance and exit of the channels were sufficient to explainthe experimentally observed anion and cation selectivity.
7 nicotinic acetylcholine receptor (nAChR) and the anionic 1 glycine receptor(GlyR), based on the structure of Torpedo nAChR. Molecular dynamics simulations were used to determinewater density profiles along the channel length, and they established that both receptor pores were fullyhydrated. The very low water density in the middle of the nAChR pore indicated the existence of ahydrophobic constriction. By contrast, the pore of GlyR was lined with hydrophilic residues and remainedwell-hydrated throughout. Adaptive biasing force simulations allowed us to reconstruct potentials of meanforce (PMFs) for chloride and sodium ions in the two receptors. For the nicotinic receptor we observedbarriers to ion translocation associated with rings of hydrophobic residues-Val13' and Leu9'-in the middleof the transmembrane domain. This finding further substantiates the hydrophobic gating hypothesis fornAChR. The PMF revealed no significant hydrophobic barrier for chloride translocation in GlyR. For bothreceptors nonpermeant ions displayed considerable barriers. Thus, the overall electrostatics and thepresence of rings of charged residues at the entrance and exit of the channels were sufficient to explainthe experimentally observed anion and cation selectivity.