Constructing ion channels from water-soluble α-helical barrels

Angstrom-scale ion channels towards single-ion selectivity

“…Specifically, hydrophobic interactions should be introduced into the interfaces between peptide residues and lipid bilayers. A rational de novo design was reported to generate a-helical barrels with polar interiors, 97 which have water-filled lumens analogous to those of transmembrane channels. Then, the sequences of a-helical barrels were modified to facilitate their accommodation in lipid bilayers.…”

Controlling Synthetic Cell-Cell Communication

“…Most current work on pore-dependent communication has employed wild-type αHL, however, other natural proteins, such as Outer membrane protein F (OmpF) ( Nikaido, 1994 ) and the Mechanosensitive channel of large conductance (MscL) ( Sukharev et al, 1997 ), or de novo designed pores, assembled from protein ( Scott et al, 2021 ; Vorobieva et al, 2021 ) or DNA ( Burns et al, 2013a ; Burns et al, 2013b ; Diederichs et al, 2019 ; Thomsen et al, 2019 ; Fragasso et al, 2021 ; Lanphere et al, 2021 ) building blocks, have also been shown to permeabilise membranes. These pores each have different sized channels, membrane preferences, and hence allow the passage of different molecules, although most are still non-selective.…”

Transient Water Wires Mediate Selective Proton Transport in Designed Channel Proteins

“…Finally, despite a few successes ( 27, 37-39 ), the design and high-resolution structural characterization of membrane proteins remains a difficult endeavor. Two de novo channel-forming proteins have been structurally characterized, but they were not highly selective, nor were their per-channel conductance rates determined ( 37, 38 ). Other work focused on the use of transition metal ion-binding to drive proton translocation and vice versa, but the anti-porting efficiency was limited by leakiness to protons ( 39 ).…”

“…Here, we not only consider water explicitly, but we also take into account the dynamic formation and breaking of covalent bonds as protons 5 are passed from one water to the next. Finally, despite a few successes (27,(37)(38)(39), the design and high-resolution structural characterization of membrane proteins remains a difficult endeavor. Two de novo channel-forming proteins have been structurally characterized, but they were not highly selective, nor were their per-channel conductance rates determined (37,38).…”