title: Blocking the passage: C60 geometrically clogs K(+) channels.
abstract: Classical molecular dynamics (MD) simulations combined with docking calculations, potential of mean force estimates with the umbrella sampling method, and molecular mechanic/Poisson-Boltzmann surface area (MM-PBSA) energy calculations reveal that C60 may block K(+) channels with two mechanisms: a low affinity blockage from the extracellular side, and an open-channel block from the intracellular side. The presence of a low affinity binding-site at the extracellular entrance of the channel is in agreement with the experimental results showing a fast and reversible block without use-dependence, from the extracellular compartment. Our simulation protocol suggests the existence of another binding site for C60 located in the channel cavity at the intracellular entrance of the selectivity filter. The escape barrier from this binding site is ∼21 kcal/mol making the corresponding kinetic rate of the order of minutes. The analysis of the change in solvent accessible surface area upon C60 binding shows that binding at this site is governed purely by shape complementarity, and that the molecular determinants of binding are conserved in the entire family of K(+) channels. The presence of this high-affinity binding site conserved among different K(+) channels may have serious implications for the toxicity of carbon nanomaterials.
authors: †Dipartimento di Chimica "G. Ciamician", Alma Mater Studiorum - Università di Bologna, via F. Selmi 2, 40126 Bologna, Italy.
authors: Matteo
authors: M
authors: Calvaresi
authors: ‡Dipartimento di Biotecnologie Mediche, Università di Siena, viale M. Bracci 12, I-53100 Siena, Italy.
authors: Simone
authors: S
authors: Furini
authors: §Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, U.K.|⊥Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, U.K.
authors: Carmen
authors: C
authors: Domene
authors: †Dipartimento di Chimica "G. Ciamician", Alma Mater Studiorum - Università di Bologna, via F. Selmi 2, 40126 Bologna, Italy.
authors: Andrea
authors: A
authors: Bottoni
authors: †Dipartimento di Chimica "G. Ciamician", Alma Mater Studiorum - Università di Bologna, via F. Selmi 2, 40126 Bologna, Italy.
authors: Francesco
authors: F
authors: Zerbetto
mesh_terms: D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D037741:Fullerenes / Q000378:metabolism / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D037741:Fullerenes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C069837:fullerene C60
keywords: K+ channels; fullerene; molecular dynamics; nanotoxicity; protein nanoparticle interaction