Ionic Liquid Gating Induces Anomalous Permeation through Membrane Channel Proteins

Area of Science:

• Biophysics
• Computational Biology
• Drug Discovery

Background:

• Membrane channel proteins (MCPs) are vital for cellular transport and drug targets.
• Ionic liquids (ILs) are emerging as potential therapeutic agents, necessitating an understanding of their interaction with MCPs.

Purpose of the Study:

• To investigate the mechanism by which ILs modulate the structure and function of MCPs.
• To elucidate the impact of ILs on water and ion transport through specific channels.

Main Methods:

• GPU-accelerated microsecond-long molecular dynamics simulations.
• Molecular trajectory and free energy analysis.
• Experimental validation using human cells and cell volume assays.

Main Results:

• ILs preferentially interact with specific MCPs, inserting into aquaporin-2 (AQP2) and adsorbing onto voltage-gated sodium channels (Nav).
• ILs minimally affect MCP structure but significantly alter transport function, decreasing the energy barrier for water through AQP2 and increasing it for Na+ through Nav.
• Permeation rates for water and Na+ were altered by at least one order of magnitude, with experimental confirmation of ILs' effect on AQP2 in human cells.

Conclusions:

• ILs exhibit an abnormal gating mechanism influencing MCP function.
• These findings deepen the understanding of IL-cell interactions and provide insights for rational drug design and disease diagnosis.