A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential

Abstract

Ion-channel function is determined by its gating movement. Yet, molecular dynamics and electrophysiological simulations were never combined to link molecular structure to function. We performed multiscale molecular dynamics and continuum electrostatics calculations to simulate a cardiac K ؉ channel (IKs) gating and its alteration by mutations that cause arrhythmias and sudden death. An all-atom model of the IKs ␣-subunit KCNQ1, based on the recent Kv1.2 structure, is used to calculate electrostatic energies during gating. Simulations are compared with experiments where varying degrees of positive charge-added via point mutationprogressively reduce current. Whole-cell simulations show that mutations cause action potential and ECG QT interval prolongation, consistent with clinical phenotypes. This framework allows integration of multiscale observations to study the molecular basis of excitation and its alteration by disease.cardiac arrhythmias ͉ long QT syndrome T he current carried by ion channels during the action potential (AP) in excitable tissues is determined by dynamic changes of the ion channel conformation during gating. Recently determined crystal structures of ion channel proteins (e.g., ref. 1) provide a structural basis for computer simulations of the ion-channel protein molecular dynamics (MD) during conformational changes. In parallel, recently acquired experimental data on ion-channel electrophysiological function have provided the basis for detailed Markov models of channel electrical function during gating (2, 3). These models can be used to link cellular consequences of genetic mutations in cardiac ion channels that alter channel kinetics to cardiac arrhythmias [see ref.4 for review]. Although consistent in reproducing the kinetics of channel opening and closing, the molecular conformations represented by the states of these Markov models are not identified.In this article, we develop a multiscale computational approach that combines molecular dynamics simulations and PoissonBoltzmann continuum electrostatic calculations with electrophysiological modeling for establishing structure-function relationships between ion channel movement during gating, its function as a carrier of transmembrane ionic current, and its role in the wholecell AP. Detailed understanding of these relationships is necessary for the development of effective genetic/molecular therapies and specific drug treatment of disease states that involve abnormal electrical function of excitable tissues. We present an example of a cardiac ion channel, the slow delayed rectifier I Ks , which participates in AP repolarization and its rate dependence (4). We consider mutations to its alpha subunit, KCNQ1, that lead to reduction of I Ks current and prolongation of the AP. The clinical phenotype associated with such mutations is the Long-QT syndrome type 1, LQT1; it presents as QT interval prolongation on the ECG and predisposes patients to cardiac arrhythmia and sudden death. Results and DiscussionSeveral charged residues that participate i...

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