Blocking the Passage: C-60 Geometrically Clogs K+ Channels

TY - JOUR

T1 - Blocking the Passage

T2 - C-60 Geometrically Clogs K+ Channels

AU - Calvaresi, Matteo

AU - Furini, Simone

AU - Domene, Carmen

AU - Bottoni, Andrea

AU - Zerbetto, Francesco

PY - 2015/5/26

Y1 - 2015/5/26

N2 - 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.

AB - 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.

KW - fullerene

KW - K+ channels

KW - nanotoxicity

KW - molecular dynamics

KW - protein nanoparticle interaction

KW - MOLECULAR-DYNAMICS SIMULATION

KW - CARBON-NANOTUBE HYBRIDS

KW - POTASSIUM CHANNEL

KW - CRYSTAL-STRUCTURE

KW - FULLERENE DERIVATIVES

KW - ELECTRON TOMOGRAPHY

KW - LIPID-MEMBRANE

KW - ION-CHANNEL

KW - PROTEINS

KW - WATER

U2 - 10.1021/nn506164s

DO - 10.1021/nn506164s

M3 - Article

SN - 1936-0851

VL - 9

SP - 4827

EP - 4834

JO - ACS Nano

JF - ACS Nano

IS - 5

ER -