Structure-activity relationship for extracellular block of K+ channels by tetraalkylammonium ions.
External tetraalkylammonium ion binding to potassium channels is studied using microscopic molecular modelling methods and the experimental structure of the KcsA channel. Relative binding free energies of the KcsA complexes with Me4N+, Et4N+, and n-Pr4N+ are calculated with the molecular dynamics free energy perturbation approach together with automated ligand docking. The four-fold symmetry of the entrance cavity formed by the Tyr82 residues is found to provide stronger binding for the D2d than for the S4 conformation of the ligands. In agreement with experiment the Et4N+ blocker shows several kcal/mol better binding than the other tetraalkylammonium ions.
Luzhkov
Victor B
VB
Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, SE-751 24 Uppsala, Sweden.
Osterberg
Fredrik
F
Aqvist
Johan
J
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels; D011485:Protein Binding; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019789:Tetraethylammonium / Q000494:pharmacology; D013816:Thermodynamics
D001426:Bacterial Proteins; D008024:Ligands; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; C107790:prokaryotic potassium channel; D019789:Tetraethylammonium