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

doi:10.1073/pnas.0904505106

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

^aDepartment of Biomedical Engineering and Cardiac Bioelectricity and Arrhythmia Center,
^bDepartment of Biochemistry, and
^cDepartment of Cell Biology and Physiology, Washington University, St. Louis, MO 63130

Communicated by Charles S. Peskin, New York University, New York, NY May 6, 2009 (received for review September 3, 2008)

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 α-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.

Footnotes

¹To whom correspondence may be addressed at:
University of Chicago, 929 East 57th Street, Chicago, IL 60637.
E-mail: jonsilva{at}gmail.com
²To whom correspondence may be sent at the present address:
Campus Box 1097, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130-1097.
E-mail: rudy{at}wustl.edu
Author contributions: J.R.S., J.C., N.A.B., D.S., and Y.R. designed research; J.R.S., H.P., D.W., A.N., and K.F.D. performed research; J.R.S., H.P., D.W., A.N., K.F.D., J.C., N.A.B., D.S., and Y.R. analyzed data; and J.R.S. and Y.R. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0904505106/DCSupplemental.
Freely available online through the PNAS open access option.