Ion channel gates: comparative analysis of energy barriers
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The energetic profile of an ion translated along the axis of an ion channel should reveal whether the structure corresponds to a functionally open or closed state of the channel. In this study, we explore the combined use of Poisson–Boltzmann electrostatic calculations and evaluation of van der Waals interactions between ion and pore to provide an initial appraisal of the gating state of a channel. This approach is exemplified by its application to the bacterial inward rectifier potassium channel KirBac3.1, where it reveals the closed gate to be formed by a ring of leucine (L124) side chains. We have extended this analysis to a comparative survey of gating profiles, including model hydrophobic nanopores, the nicotinic acetylcholine receptor, and a number of potassium channel structures and models. This enables us to identify three gating regimes, and to show the limitation of this computationally inexpensive method. For a (closed) gate radius of 0.4 nm < R < 0.8 nm, a hydrophobic gate may be present. For a gate radius of 0.2 nm < R < 0.4 nm, both electrostatic and van der Waals interactions will contribute to the barrier height. Below R = 0.2 nm, repulsive van der Waals interactions are likely to dominate, resulting in a sterically occluded gate. In general, the method is more useful when the channel is wider; for narrower channels, the flexibility of the protein may allow otherwise-unsurmountable energetic barriers to be overcome.
KeywordsIon channel Gate Electrostatics Model Simulation
Large-conductance mechanosensitive channel
Small-conductance mechanosensitive channel
Nicotinic acetylcholine receptor
Potential of mean force
We thank Shiva Amiri, Kia Balali-Mood, Oliver Beckstein, Phil Biggin, John Holyoake, and Phill Stansfeld for helpful discussions; Nathan Baker and Jens Erik Nielsen for the APBS and PDB2PQR software. This work is supported by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.
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