Brownian dynamics theory for predicting internal and external blockages of tetraethylammonium in the KcsA potassium channel

Matthew Hoyles, Vikram Krishnamurthy, May Siksik, Shin Ho Chung*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    10 Citations (Scopus)


    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 ki 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 ∼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.

    Original languageEnglish
    Pages (from-to)366-378
    Number of pages13
    JournalBiophysical Journal
    Issue number2
    Publication statusPublished - 15 Jan 2008


    Dive into the research topics of 'Brownian dynamics theory for predicting internal and external blockages of tetraethylammonium in the KcsA potassium channel'. Together they form a unique fingerprint.

    Cite this