Abstract
Ion channels are the “building blocks” of the excitation process in excitable tissues. Despite advances in determining their molecular structure, understanding the relationship between channel protein structure and electrical excitation remains a challenge. The Kv7.1 potassium channel is an important determinant of the cardiac action potential and its adaptation to rate changes. It is subject to beta adrenergic regulation, and many mutations in the channel protein are associated with the arrhythmic long QT syndrome. In this theoretical study, we use a novel computational approach to simulate the conformational changes that Kv7.1 undergoes during activation gating and compute the resulting electrophysiologic function in terms of single-channel and macroscopic currents. We generated all possible conformations of the S4–S5 linker that couples the S3–S4 complex (voltage sensor domain, VSD) to the pore, and all associated conformations of VSD and the pore (S6). Analysis of these conformations revealed that VSD-to-pore mechanical coupling during activation gating involves outward translation of the voltage sensor, accompanied by a translation away from the pore and clockwise twist. These motions cause pore opening by moving the S4–S5 linker upward and away from the pore, providing space for the S6 tails to move away from each other. Single channel records, computed from the simulated motion trajectories during gating, have stochastic properties similar to experimentally recorded traces. Macroscopic current through an ensemble of channels displays two key properties of Kv7.1: an initial delay of activation and fast inactivation. The simulations suggest a molecular mechanism for fast inactivation; a large twist of the VSD following its outward translation results in movement of the base of the S4–S5 linker toward the pore, eliminating open pore conformations to cause inactivation.
Highlights
Membrane ion channels are the fundamental molecular “building blocks” of the excitation process in excitable tissues
We developed a general computational-biology approach for simulating the structural dynamics of an ion channel protein during gating and the resulting function in terms of channel current (Nekouzadeh and Rudy, 2011a). This new method is based on physical principles and designed to simulate the large and gradual intra-molecular motions of macromolecules over the milliseconds time scale of gating and other biophysical processes that determine the multi-scale physiological system behavior (Gjuvsland et al, 2013). It differs from the conventional Molecular Dynamics (MD) computational approach, which simulates atomic-level motions over much shorter time scales
The VSD is in an outward position and the S4– S5 linker is positioned horizontally; the S6 tail is located under the S4–S5 linker
Summary
Membrane ion channels are the fundamental molecular “building blocks” of the excitation process in excitable tissues. We developed a general computational-biology approach for simulating the structural dynamics of an ion channel protein during gating and the resulting function in terms of channel current (Nekouzadeh and Rudy, 2011a). This new method is based on physical principles and designed to simulate the large and gradual intra-molecular motions of macromolecules over the milliseconds time scale of gating and other biophysical processes that determine the multi-scale physiological system behavior (Gjuvsland et al, 2013). The current through ion-channels is controlled by the stochastic pattern of channel opening and closing (Nekouzadeh and Rudy, 2007a; Nekouzadeh and Rudy, 2007b), which is a consequence of conformational alterations within the ion-channel protein (Broomand and Elinder, 2008; Doyle, 2004; Gandhi et al, 2003; Gulbis and Doyle, 2004; Jiang et al, 2003; Long et al, 2005b; Nekouzadeh and Rudy, 2011a; Nishizawa and Nishizawa, 2009; Perozo, 2002; Perozo et al, 1999; Posson and Selvin, 2008; Ruta et al, 2005; Sansom and Weinstein, 2000; Silva et al, 2009; Tieleman et al, 2001)
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