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

@article{citeulike:5043715, 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 (I(Ks)) gating and its alteration by mutations that cause arrhythmias and sudden death. An all-atom model of the I(Ks) alpha-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 mutation-progressively 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.}, author = {Silva, Jonathan R. and Pan, Hua and Wu, Dick and Nekouzadeh, Ali and Decker, Keith F. and Cui, Jianmin and Baker, Nathan A. and Sept, David and Rudy, Yoram}, citeulike-article-id = {5043715}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0904505106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/27/11102.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/27/11102.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19549851}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19549851}, day = {7}, doi = {10.1073/pnas.0904505106}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {dynamics, electrophysiology, gating, molecular, silva09pdf}, month = {July}, number = {27}, pages = {11102--11106}, posted-at = {2009-07-08 01:47:51}, priority = {2}, title = {A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential.}, url = {http://dx.doi.org/10.1073/pnas.0904505106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:5043715 L3 - citeulike-article-id:5043715 N2 - 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 (I(Ks)) gating and its alteration by mutations that cause arrhythmias and sudden death. An all-atom model of the I(Ks) alpha-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 mutation-progressively 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. IS - 27 JF - Proceedings of the National Academy of Sciences of the United States of America SN - 1091-6490 EP - 11106 TI - A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential. VL - 106 SP - 11102 KW - dynamics KW - electrophysiology KW - gating KW - molecular KW - silva09pdf AU - Silva, Jonathan AU - Pan, Hua AU - Wu, Dick AU - Nekouzadeh, Ali AU - Decker, Keith AU - Cui, Jianmin AU - Baker, Nathan AU - Sept, David AU - Rudy, Yoram PY - 2009/07/07/ UR - http://dx.doi.org/10.1073/pnas.0904505106 ER -