Brownian Dynamics Theory for Predicting Internal and External Blockages of Tetraethylammonium in the KcsA Potassium Channel

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dc.contributor.authorHoyles, Matthew
dc.contributor.authorKrishnamurthy, Vikram
dc.contributor.authorSiksik, May
dc.contributor.authorChung, Shin-Ho
dc.date.accessioned2016-03-29T03:45:48Z
dc.date.available2016-03-29T03:45:48Z
dc.date.issued2008-11-12
dc.date.updated2016-06-14T09:18:50Z
dc.description.abstractThe 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.
dc.description.sponsorshipThis work was supported by grants from the National Health & Medical Research Council of Australia.en_AU
dc.identifier.issn0006-3495en_AU
dc.identifier.urihttp://hdl.handle.net/1885/100901
dc.publisherBiophysical Society
dc.rights© 2008 by the Biophysical Society.
dc.sourceBiophysical Journal
dc.subjectalgorithms
dc.subjectcomputational biology
dc.subjectkinetics
dc.subjectpotassium
dc.subjectpotassium channels
dc.subjectprotein subunits
dc.subjecttetraethylammonium
dc.subjectthermodynamics
dc.subjectmodels, chemical
dc.titleBrownian Dynamics Theory for Predicting Internal and External Blockages of Tetraethylammonium in the KcsA Potassium Channel
dc.typeJournal article
local.bibliographicCitation.issue2en_AU
local.bibliographicCitation.lastpage378en_AU
local.bibliographicCitation.startpage366en_AU
local.contributor.affiliationHoyles, Matthew, College of Medicine, Biology and Environment, CMBE Research School of Biology, RSB General, The Australian National Universityen_AU
local.contributor.affiliationKrishnamurthy, Vikram, University of British Columbia, Canadaen_AU
local.contributor.affiliationSiksik, May, University of British Columbia, Canadaen_AU
local.contributor.affiliationChung, Shin-Ho, College of Medicine, Biology and Environment, CMBE Research School of Biology, RSB General, The Australian National Universityen_AU
local.contributor.authoremailShin-Ho.Chung@anu.edu.auen_AU
local.contributor.authoruidu8809509en_AU
local.description.notesImported from ARIESen_AU
local.identifier.absfor060110en_AU
local.identifier.absfor060199en_AU
local.identifier.ariespublicationu9204316xPUB419en_AU
local.identifier.citationvolume94en_AU
local.identifier.doi10.1529/biophysj.107.115139en_AU
local.identifier.essn1542-0086en_AU
local.identifier.scopusID2-s2.0-38349008876
local.identifier.uidSubmittedByu3488905en_AU
local.publisher.urlhttp://www.biophysics.org/en_AU
local.type.statusPublished Versionen_AU

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