title: Energetics of Ion Permeation in an Open-Activated TRPV1 Channel.
abstract: Ion channels enable diffusion of ions down physiological electrochemical gradients. Modulation of ion permeation is crucial for the physiological functioning of cells, and misregulation of ion channels is linked to a myriad of channelopathies. The ion permeation mechanism in the transient receptor potential (TRP) ion channel family is currently not understood at an atomistic level. In this work, we employed a simulation strategy for ion permeation (molecular-dynamics simulations with bias-exchange metadynamics) to study and compare monovalent (Na(+), K(+)) ion permeation in the open-activated TRP vanniloid-1 (TRPV1) ion channel. Using ∼3.6 μs of simulation trajectories, we obtained atomistic evidence for the nonselective nature of TRPV1. Our analysis shows that solvated monovalent ions permeate through the selectivity filter with comparable energetic barriers via a two-site mechanism. Finally, we confirmed that an intracellular binding site is located between the intracellular gate residues I679 and E684.
authors.affiliation: Department of Chemistry, King's College London, London, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Furini
authors.affiliation: Department of Chemistry, King's College London, London, United Kingdom; Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom. Electronic address: carmen.domene@kcl.ac.uk.
authors.forename: Carmen
authors.initials: C
authors.lastname: Domene
mesh_terms: D000818:Animals; D001665:Binding Sites; D002414:Cations, Monovalent / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000737:chemistry*; D011487:Protein Conformation; D012964:Sodium / Q000737:chemistry*; D050916:TRPV Cation Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D002414:Cations, Monovalent; D050916:TRPV Cation Channels; D012964:Sodium; D011188:Potassium