"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 (PA₆₃), it appears as fast voltage-independent current interruptions between conducting and nonconducting states. This behavior hampers potential development of PA₆₃ as an ion-channel biosensor. On the bright side, the PA₆₃ 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 PA₆₃, 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 PA₆₃ 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 PA₆₃ 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 PA₆₃ 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.

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