Ion Permeation, Selectivity, and Electronic Polarization in Fluoride Channels

Abstract

Fluoride channels (Fluc) export toxic F- from the cytoplasm. Crystallography and mutagenesis have identified several conserved residues crucial for fluoride transport, but the transport mechanism at the molecular level has remained elusive. Herein we have applied constant-pH molecular dynamics and free energy sampling methods to investigate fluoride transfer through a Fluc protein from Escherichia coli. We find that fluoride is facile to transfer in its charged form, i.e., F-, by traversing through a non-bonded network. The extraordinary F- selectivity is gained by the hydrogen-bonding capability of the central binding site and the Coulombic filter at the channel entrance. The F- transfer rate calculated using an electronically polarizable force field is significantly more accurate compared to the experimental value than that calculated using a more standard additive force field, suggesting an essential role for electronic polarization in the F- - Fluc interactions.

Uncovering the Mechanism of the Proton-Coupled Fluoride Transport in the CLCF Antiporter

“…The PMFs calculated here result in energy barriers of 0.1-2.6 kcal/mol, which is comparable to the PMFs previously reported for the CLC Cl -/H + antiporter which gave energy barriers of between 2 and 4 kcal/mol. 42,43 Additionally, we have shown that CLC F is transporting fluoride as an anion and not as HF, as the latter creates very large energy barriers for the system to overcome, a result which complements the recent work by Yue et al 36 on the Fluc Fchannel. This work is among the first reported computational studies of the CLC F antiporter protein, and is the first to propose a mechanism to couple the proton import with Fexport.…”

“…42,43 Additionally, we have shown that CLC F is transporting fluoride as an anion and not as HF, as the latter creates very large energy barriers for the system to overcome, a result which complements the recent work by Yue et al . 36 on the Fluc F - channel.…”

“…The force field parameters for HF used were previously reported by Laage et al 35 and used for similar calculations by Yue et al . 36 6…”

Hydrated anions: From clusters to bulk solution with quasi-chemical theory

“…29-38. But computational studies of anion transport mechanisms demonstrated by chloride-selective channels [39][40][41][42] that address comparison to alternatives such as FLUC are less mature. 3,43 A conceptually natural strategy to address ion selectivity with computation would be direct simulations controlling for the contrasting cases, or perhaps a clear, quantitative theory that permits controlling for mechanistic features of the ion binding or transport. Both of these requests are difficult.…”