Probability Fluxes and Transition Paths in a Markovian Model Describing Complex Subunit Cooperativity in HCN2 Channels 英文参考文献.docVIP

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Probability Fluxes and Transition Paths in a Markovian Model Describing Complex Subunit Cooperativity in HCN2 Channels 英文参考文献.doc

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Probability Fluxes and Transition Paths in a Markovian Model Describing Complex Subunit Cooperativity in HCN2 Channels 英文参考文献

ProbabilityFluxesandTransitionPathsinaMarkovian ModelDescribingComplexSubunitCooperativityin HCN2Channels KlausBenndorf1*,JanaKusch1,EckhardSchulz2 1Friedrich-Schiller-Universita¨t Jena, Universita¨tsklinikum Jena, Institut fu¨r Physiologie II, Jena, Germany, 2Fachhochschule Schmalkalden, Fakulta¨t Elektrotechnik, Blechhammer,Schmalkalden,Germany Abstract Hyperpolarization-activatedcyclicnucleotide-modulated(HCN)channelsarevoltage-gatedtetramericcationchannelsthat generateelectricalrhythmicityinneuronsandcardiomyocytes.Activationcanbeenhancedbythebindingofadenosine- 39,59-cyclicmonophosphate(cAMP)toanintracellularcyclicnucleotidebindingdomain.Basedonpreviouslydetermined rate constants for a complex Markovian model describing the gating of homotetrameric HCN2 channels, we analyzed probability fluxes within this model, including unidirectional probability fluxes and the probability flux along transition paths. The time-dependent probability fluxes quantify the contributions of all 13 transitions of the model to channel activation. The binding of the first, third and fourth ligand evoked robust channel opening whereas the binding of the secondligandobstructedchannelopeningsimilartotheemptychannel.Analysisofthenetprobabilityfluxesintermsof thetransitionpaththeoryrevealedpronounced hysteresis forchannelactivationanddeactivation.Theseresultsprovide quantitative insight into the complex interaction of the four structurally equal subunits, leading to non-equality in their function. Citation:BenndorfK,KuschJ,SchulzE(2012)ProbabilityFluxesandTransitionPathsinaMarkovianModelDescribingComplexSubunitCooperativityinHCN2 Channels.PLoSComputBiol8(10):e1002721.doi:10.1371/journal.pcbi.1002721 Editor:MarkS.Alber,UniversityofNotreDame,UnitedStatesofAmerica ReceivedMay18,2012;AcceptedAugust16,2012;PublishedOctober18,2012 Copyright: ? 2012 Benndorf et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricte