Conformational Change from U- to I-Shape of Ion Transporters Facilitates K⁺ Transport across Lipid Bilayers

Abstract

We have investigated, at the atomic level, the ion-fishing mechanism underlying the ion transport across membranes mediated by an artificial ion transporter composed of a hydroxyl-rich cholesterol group, a flexible alkyl chain, and a crown ether. Our results show that the transporter can spontaneously insert into the membrane and switch between the folded (U-shaped) and extended (I-shaped) conformations. The free-energy profile associated with the conformational transition indicates that compared with the U-shaped conformation of the transporter, the I-shaped one is thermodynamically more favorable. Furthermore, the free-energy profiles describing the ion translocation reveal that the transporter capturing the ion in U-shape on one side of the membrane and releasing it in I-shape on the other side constitutes a key way for the highly efficient transport of K+ ions. We present herewith a rigorous and rational framework to decipher the detailed ion-fishing mechanism of transmembrane ion transport with exceptionally high activity.

Artificial transmembrane potassium transporters: designs, functions, mechanisms and applications

“…90 The multistep catch-and-release ion-fishing cycle was originally envisioned by us and later exactly reproduced by Shao and Cai using a molecular dynamics simulation approach. 91 Among eight MFs studied, except for MF5-C14 that is weakly Na +selective, the remaining seven MFs all are K + -selective, with MF6-C8 and MF6-C14 exhibiting the highest K + transport activity (EC 50 = 0.37 mol% relative to the lipids) and the highest K + /Na + selectivity of 18.3, respectively. It is interesting to note that all MFs do not transport Li + ions and that ion transport efficiencies of molecular ion fishers MFs generally are not as good as molecular swings MSs.…”

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications

“…Miao, Shao, and Cai used MD simulations to study an ion transporter consisting of a single molecule spanning the lipid bilayer. 285 MD simulations show that the artificial transporter translocates K + ions through alternating U-shape and linear shapes. The free energy of the transporter conformation in the membrane was then calculated using MD simulations.…”

“…MD simulations were used to model the assembly and ligand binding to the polymer ion channel. Miao, Shao, and Cai used MD simulations to study an ion transporter consisting of a single molecule spanning the lipid bilayer . MD simulations show that the artificial transporter translocates K + ions through alternating U-shape and linear shapes.…”

Molecular Machines For The Control Of Transmembrane Transport

“…100,102 A computational study found that Hbonding between the cholesterol and the phosphate of a lipid restricted lateral translocation, rationalizing the efficiency of this anchor group. 103 Interestingly, after prolonged investigations, no single-channel current traces were obtained for the moncholesterol 16 or a bis-cholesterol anchored system in BLM conductance experiments, indicating that ions were not transported through well-defined channels. 99,102 Ill-defined and transient single-channel current traces were observed for the molecular swing transporter 17 in BLM experiments.…”

“…Zeng and co-workers have been pioneers in this area, developing transport system 16 (Figure ), a so-called “molecular ion fisher.” The cholesterol unit was used to anchor the system, while the flexible linker to the benzo-18-crown-6 K + binding motif facilitated transport by this unconventional mechanism . Transporters with different anchoring architectures have been reported, based on a single cholesterol lock, as well as systems with a membrane-spanning cross-beam containing two cholesterol units 17 . , A computational study found that H-bonding between the cholesterol and the phosphate of a lipid restricted lateral translocation, rationalizing the efficiency of this anchor group . Interestingly, after prolonged investigations, no single-channel current traces were obtained for the moncholesterol 16 or a bis-cholesterol anchored system in BLM conductance experiments, indicating that ions were not transported through well-defined channels. , Ill-defined and transient single-channel current traces were observed for the molecular swing transporter 17 in BLM experiments .…”