title: In silico analysis of conformational changes induced by mutation of aromatic binding residues: consequences for drug binding in the hERG K+ channel.
abstract: Pharmacological inhibition of cardiac hERG K(+) channels is associated with increased risk of lethal arrhythmias. Many drugs reduce hERG current by directly binding to the channel, thereby blocking ion conduction. Mutation of two aromatic residues (F656 and Y652) substantially decreases the potency of numerous structurally diverse compounds. Nevertheless, some drugs are only weakly affected by mutation Y652A. In this study we utilize molecular dynamics simulations and docking studies to analyze the different effects of mutation Y652A on a selected number of hERG blockers. MD simulations reveal conformational changes in the binding site induced by mutation Y652A. Loss of π-π-stacking between the two aromatic residues induces a conformational change of the F656 side chain from a cavity facing to cavity lining orientation. Docking studies and MD simulations qualitatively reproduce the diverse experimentally observed modulatory effects of mutation Y652A and provide a new structural interpretation for the sensitivity differences.
authors.affiliation: Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Knape
authors.forename: Tobias
authors.initials: T
authors.lastname: Linder
authors.forename: Peter
authors.initials: P
authors.lastname: Wolschann
authors.forename: Anton
authors.initials: A
authors.lastname: Beyer
authors.forename: Anna
authors.initials: A
authors.lastname: Stary-Weinzinger
mesh_terms: D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic / Q000235:genetics*; D002211:Capsaicin / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D018583:Pliability; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D055550:Protein Stability; D013816:Thermodynamics
chemical_list: D024322:Amino Acids, Aromatic; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D050505:Mutant Proteins; D026902:Potassium Channel Blockers; D002211:Capsaicin