Microsecond Pore Dilation Kinetics and Hydrophobic Gating of Magnesium Transport in the Cora System

Abstract

Although magnesium homeostasis is essential for life, the mechanism by which cells select Mg2+ among more prevalent biological ions like Na+ and K+ is unknown. In our earlier molecular dynamics (MD) simulation study [Chakrabarti et al., An Iris-like Mechanism of Pore Dilation in the CorA Magnesium Transport System, Biophys. J. (2010) 98: 784-792], we identified a 1.5-nm-long hydrophobic constriction in the CorA Mg2+ transport system which is dehydrated in the crystallographic state of the channel. In our simulations, an iris-like dilation of the pore led to a rapid wetting transition of the hydrophobic bottleneck, but only after regulatory magnesium ions were removed from their intracellular binding sites. Here we report large-scale atomistic simulations of CorA in a hydrated bilayer successively with and without regulatory ions. The results of hundreds of simulations confirm the allosteric mechanism linking the ionic occupancy of the regulatory sites to hydrophobic gating of the pore and provide quantitative insight into the early kinetics of pore dilation and hydration. Free energy simulations for magnesium permeation through a relatively dilated conformation of the channel are presented, and the interplay of hydration, ionic occupancy of the lumen, and structural fluctuations of the channel are analyzed. Together, these results provide insight into the molecular mechanisms governing the regulation, transport, and selectivity of magnesium permeation in the unusually long channel lumen of CorA.