Hydrophobic Gating and 1/f Noise of the Anthrax Toxin Channel

Abstract

Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: "Pink" or 1/f noise is a natural phenomenon omnipresent in physics, economics, astrophysics, biology, and even music and languages. In electrophysiology, the stochastic activity of a number of biological ion channels and artificial nanopores could be characterized by current noise with a 1/f power spectral density. In the anthrax toxin channel (PA 63 ), it appears as fast voltage-independent current interruptions between conducting and nonconducting states. This behavior hampers potential development of PA 63 as an ionchannel biosensor. On the bright side, the PA 63 flickering represents a mesmerizing phenomenon to investigate. Notably, similar 1/f fluctuations are observed in the channel-forming components of clostridial binary C2 and iota toxins, which share functional and structural similarities with the anthrax toxin channel. Similar to PA 63 , they are evolved to translocate the enzymatic components of the toxins into the cytosol. Here, using high-resolution single-channel lipid bilayer experiments and all-atom molecular dynamic simulations, we suggest that the 1/f noise in PA 63 occurs as a result of "hydrophobic gating" at the ϕ-clamp region, the phenomenon earlier observed in several water-filled channels "fastened" inside by the hydrophobic belts. The ϕ-clamp is a narrow "hydrophobic ring" in the PA 63 lumen formed by seven or eight phenylalanine residues at position 427, conserved in the C2 and iota toxin channels, which catalyzes protein translocation. Notably, the 1/f noise remains undetected in the F427A PA 63 mutant. This finding can elucidate the functional purpose of 1/f noise and its possible role in the transport of the enzymatic components of binary toxins.

Cryo-EM structures of the translocational binary toxin complex CDTa-bound CDTb-pore from Clostridioides difficile

“…The φ-clamp structures seem stable in the same con guration as closed (6-Å diameter) in all reported structures of CDTb, Ib, and PA, and no other open conformation was observed. However, two assumed open-states have been observed in electrophysiological studies 43,45 . To address this, the high-resolution structure of the translocation complex needs to be clari ed.…”

Synthesis, computational docking and molecular dynamics studies of a new class of spiroquinoxalinopyrrolidine embedded chromanone hybrids as potent anti-cholinesterase agents

“…The short-range non-bonding (van der Waals (vdW) and Coulomb) interactions are computed with a cut-off of 1.2 nm, and long-range electrostatic interactions were computed using the Particle-Mesh-Ewald (PME) 55 method. The above-mentioned MD protocol was used to obtain the stable MD trajectories of various systems [56][57][58][59][60][61][62] involving proteins and lipid membranes. Various structural properties, such as nal snapshots, RMSDs, RMSF, RMSD per residue, number of hydrogen bonds, free-energy landscape (FELs), protein-ligand interactions, and binding energies, were obtained by analyzing production MD trajectories.…”