Page 45 - Cardiac Electrophysiology | A Modeling and Imaging Approach

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Pore Energy and Subconductances (SC) of I
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To compute the channel function in terms of microscopic (single-channel) and macro-
scopic current, the subconductance (SC) of each structural cluster is calculated. A representative
structure from each cluster was used to calculate the energy profile across the pore (Figure

2.27A). This pore-energy profile (energy barrier) would affect the probability of an ion passing
through the pore (P ). The peak of the energy barrier (located at the activation gate in the pore)
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was used to construct the pore energy map (Figure 2.27A, center). This map shows the peak
energy barrier as a function of voltage-sensor position and pore diameter. Note that

conformations with high voltage sensor position and large pore diameter are associated with
a low energy barrier (white triangle on the pore-energy map) and therefore large P , while
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structures with low voltage sensor position and small pore diameter are associated with a high
energy barrier (white asterisk on the map) and small P . The SC are proportional to P . Figure
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2.27B shows the SC map computed from the pore-energy map. Clusters 1 and 5 have the highest
SC, while cluster 3 has the lowest SC. Note that the SC is affected not only by the pore diameter,
but also by the voltage-sensor position. Gating conformations with S4 at higher Z have lower
energy barrier at the pore because the repulsive electrostatic field in the pore, influenced by the

four positively charged S4 segments, is mitigated by the shielding effects of the surrounding
protein segments and water at higher S4 Z positions.

Simulations of I Function from the Structural Dynamics
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The SC map was used to simulate I function as current carrier (Figure 2.28). The
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simulated currents were compared to experiments under similar conditions and protocols 123a .
Simulated single-channel current traces and macroscopic current (average of 100 single-channel

traces) showed good correspondence with experimental data (Figure 2.28A and B). SC levels,
accessed during activation, were equivalent to experimental measurements (Figure 2.28C). The
simulated mean single-channel current amplitudes at different depolarized V were used to
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calculate the microscopic current – voltage (I – V) relationship; an example at V = 60 mV is shown
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in Figure 2.28D. The I – V curve shows excellent correlation with experimental recordings (Figure
2.28E). Similar to experiments, simulations produced many silent single-channel traces where I
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structural changes did not result in conducting pore conformations. Single-channel
characteristics (latency to first opening, total dwell time, mean open time, and first opening

probability) were consistent with experimental values. Simulated single-channel traces showed
increased access to high SC levels with larger depolarizing V .
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Two Distinct Voltage-Sensor Movements

Analysis of 2000 I trajectories during activation identified two voltage-sensor movements,
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at negative and positive V (Figure 2.29, red trace), consistent with fluorescence experiments 123b .
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