Proton transport pathway in the ClC Cl-/H+ antiporter.
A fundamental question concerning the ClC Cl-/H+ antiporters is the nature of their proton transport (PT) pathway. We addressed this issue by using a novel computational methodology capable of describing the explicit PT dynamics in the ClC-ec1 protein. The main result is that the Glu203 residue delivers a proton from the intracellular solution to the core of ClC-ec1 via a rotation of its side chain and subsequent acid dissociation. After reorientation of the Glu203 side chain, a transient water-mediated PT pathway between Glu203 and Glu148 is established that is able to receive and translocate the proton via Grotthuss shuttling after deprotonation of Glu203. A molecular-dynamics simulation of an explicit hydrated excess proton in this pathway suggests that a negatively charged Glu148 and the central Cl- ion act together to drive H+ to the extracellular side of the membrane. This finding is consistent with the experimental result that Cl- binding to the central site facilitates the proton movement. A calculation of the PT free-energy barrier for the ClC-ec1 E203V mutant also supports the proposal that a dissociable residue is required at this position for efficient delivery of H+ to the protein interior, in agreement with recent experimental results.
Wang
Dong
D
Center for Biophysical Modeling and Simulation, and Department of Chemistry, University of Utah, Salt Lake City, Utah, USA.
Voth
Gregory A
GA
D000595:Amino Acid Sequence; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology*; D003198:Computer Simulation; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D011522:Protons; D014867:Water / Q000378:metabolism
D017920:Antiporters; D011522:Protons; D014867:Water