Calvaresi, Matteo; Furini, Simone; Domene, Carmen; Bottoni, Andrea; Zerbetto, Francesco
Blocking the Passage: C-60 Geometrically Clogs K+ Channels
ACS NANO, 9:4827-4834, MAY 2015

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 C-60 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 C-60 located in the channel cavity at the intracellular entrance of the selectivity filter. The escape barrier from this binding site is similar to 21 kcal/mol making the corresponding kinetic rate of the order of minutes. The analysis of the change in solvent accessible surface area upon C-60 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.


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