Thermodynamics of ion binding and occupancy in potassium channels

Jing, Zhifeng; Rackers, Joshua A.; Pratt, Lawrence R.; Liu, Chengwen; Rempe, Susan B.; Ren, Pengyu

doi:10.1039/d1sc01887f

Thermodynamics of ion binding and occupancy in potassium channels

Journal Article · 02 June 2021 · Chemical Science

DOI:https://doi.org/10.1039/d1sc01887f· OSTI ID:1786837

^[1]; Rackers, Joshua A. ^[2]; Pratt, Lawrence R. ^[3]; ^[1]; Rempe, Susan B. ^[2]; Ren, Pengyu ^[1]

Univ. of Texas, Austin, TX (United States)
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Tulane Univ., New Orleans, LA (United States)

Potassium channels modulate various cellular functions through efficient and selective conduction of K⁺ ions. The mechanism of ion conduction in potassium channels has recently emerged as a topic of debate. Crystal structures of potassium channels show four K⁺ ions bound to adjacent binding sites in the selectivity filter, while chemical intuition and molecular modeling suggest that the direct ion contacts are unstable. Molecular dynamics (MD) simulations have been instrumental in the study of conduction and gating mechanisms of ion channels. Based on MD simulations, two hypotheses have been proposed, in which the four-ion configuration is an artifact due to either averaged structures or low temperature in crystallographic experiments. The two hypotheses have been supported or challenged by different experiments. Here, MD simulations with polarizable force fields validated by ab initio calculations were used to investigate the ion binding thermodynamics. Contrary to previous beliefs, the four-ion configuration was predicted to be thermodynamically stable after accounting for the complex electrostatic interactions and dielectric screening. Polarization plays a critical role in the thermodynamic stabilities. As a result, the ion conduction likely operates through a simple single-vacancy and water-free mechanism. The simulations explained crystal structures, ion binding experiments and recent controversial mutagenesis experiments. This work provides a clear view of the mechanism underlying the efficient ion conduction and demonstrates the importance of polarization in ion channel simulations.

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Research Organization:: Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC04-94AL85000; NA0003525; NA-0003525

OSTI ID:: 1786837

Alternate ID(s):: OSTI ID: 1810365

Report Number(s):: SAND-2021-8299J; 697216

Journal Information:: Chemical Science, Vol. 12, Issue 25; ISSN 2041-6520

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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Thermodynamics of ion binding and occupancy in potassium channels

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