title: Brownian dynamics theory for predicting internal and external blockages of tetraethylammonium in the KcsA potassium channel.
abstract: The theory of Brownian dynamics is used to model permeation and the blocking of KcsA potassium channels by tetraethylammonium (TEA). A novel Brownian dynamics simulation algorithm is implemented that comprises two free energy profiles; one profile is seen by the potassium ions and the other by the TEA molecules whose shape is approximated by a sphere. Our simulations reveal that internally applied TEA blocks the passage of K(+) ions by physically occluding the pore. A TEA molecule in the external reservoir encounters an attractive energy-well created by four tyrosine residues at position 82, in addition to all other attractive and repulsive forces impinging on it. Using Brownian dynamics, we investigate how deep the energy-well needs to be to reproduce the experimentally determined inhibitory constant k(i) for the TEA blockade of KcsA or the mutant Shaker T449Y. The one-dimensional free energy profile obtained from molecular dynamics is first converted into a one-dimensional potential energy profile, and is then transformed into a three-dimensional free energy profile in Brownian dynamics by adding the short-range potential from the channel walls. When converted, the free energy profile calculated from molecular dynamics gives a well-depth of approximately 10 kT. We systematically alter the depths of the profiles, and then use Brownian dynamics simulations to numerically determine the current versus TEA-concentration curves. We show that the sequence of binding and unbinding events of the TEA molecule to the binding pocket can be modeled by a first-order Markov process. The Brownian dynamics simulations also reveal that the probability of a TEA molecule binding to the binding pocket in KcsA potassium channels increases exponentially with TEA concentration and depends also on the applied potential and the K(+) concentration in the simulation assembly.
authors.affiliation: Research School of Biological Sciences, The Australian National University, Canberra, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoyles
authors.forename: Vikram
authors.initials: V
authors.lastname: Krishnamurthy
authors.forename: May
authors.initials: M
authors.lastname: Siksik
authors.forename: Shin-Ho
authors.initials: SH
authors.lastname: Chung
mesh_terms: D000465:Algorithms; D019295:Computational Biology; D007700:Kinetics; D008956:Models, Chemical; D011188:Potassium; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry; D019789:Tetraethylammonium / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D015221:Potassium Channels; D021122:Protein Subunits; D019789:Tetraethylammonium; D011188:Potassium