title: Drying transition in the hydrophobic gate of the GLIC channel blocks ion conduction.
abstract: The theoretical prediction of water drying transitions near nonpolar surfaces has stimulated an intensive search for biological processes exploiting this extreme form of hydrophobicity. Here we quantitatively demonstrate that drying of a hydrophobic constriction is the major determinant of ion conductance in the GLIC pentameric ion channel. Molecular-dynamics simulations show that in the closed state, the channel conductance is ∼12 orders-of-magnitude lower than in the open state. This large drop in conductance is remarkable because even in the functionally closed conformation the pore constriction remains wide enough for the passage of sodium ions, aided by a continuous bridge of ∼12 water molecules. However, we find that the free energy cost of hydrating the hydrophobic gate is large, accounting almost entirely for the energetic barrier blocking ion passage. The free energies of transferring a sodium ion into a prehydrated gate in functionally closed and open states differ by only 1.2 kcal/mol, compared to an 11 kcal/mol difference in the costs of hydrating the hydrophobic gate. Conversely, ion desolvation effects play only minor roles in GLIC ion channel gating. Our simulations help rationalize experiments probing the gating kinetics of the nicotinic acetylcholine receptor in response to mutations of pore-lining residues. The molecular character and phase behavior of water should thus be included in quantitative descriptions of ion channel gating.
authors.affiliation: Department of Physics, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA. fzhu0@iupui.edu
authors.forename: Fangqiang
authors.initials: F
authors.lastname: Zhu
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hummer
mesh_terms: D003890:Desiccation; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D007473:Ion Channels