title: Hydrophobic Gating of Ion Permeation in Magnesium Channel CorA.
abstract: Ion channels catalyze ionic permeation across membranes via water-filled pores. To understand how changes in intracellular magnesium concentration regulate the influx of Mg2+ into cells, we examine early events in the relaxation of Mg2+ channel CorA toward its open state using massively-repeated molecular dynamics simulations conducted either with or without regulatory ions. The pore of CorA contains a 2-nm-long hydrophobic bottleneck which remained dehydrated in most simulations. However, rapid hydration or "wetting" events concurrent with small-amplitude fluctuations in pore diameter occurred spontaneously and reversibly. In the absence of regulatory ions, wetting transitions are more likely and include a wet state that is significantly more stable and more hydrated. The free energy profile for Mg2+ permeation presents a barrier whose magnitude is anticorrelated to pore diameter and the extent of hydrophobic hydration. These findings support an allosteric mechanism whereby wetting of a hydrophobic gate couples changes in intracellular magnesium concentration to the onset of ionic conduction.
authors.affiliation: Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Neale
authors.affiliation: Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Nilmadhab
authors.initials: N
authors.lastname: Chakrabarti
authors.affiliation: Shared Hierarchical Academic Research Computing Network, Department of Physics and Astronomy, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Pawel
authors.initials: P
authors.lastname: Pomorski
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Ontario Cancer Institute/Princess Margaret Cancer Centre, Campbell Family Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Emil F
authors.initials: EF
authors.lastname: Pai
authors.affiliation: Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Régis
authors.initials: R
authors.lastname: Pomès
mesh_terms: D027682:Cation Transport Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating; D007477:Ions / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D010539:Permeability; D014867:Water / Q000737:chemistry*; D017155:Wettability
chemical_list: D027682:Cation Transport Proteins; C514433:CorA protein, E coli; D029968:Escherichia coli Proteins; D007477:Ions; D014867:Water; D008274:Magnesium