Journal of the American Chemical Society
Journal of the American Chemical Society
5 years ago

The Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory

The Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory
Piao Ma, Alfredo E. Cardenas, Ron Elber, Mangesh I. Chaudhari, Susan B. Rempe
We report atomically detailed molecular dynamics simulations of the permeation of the lethal factor (LF) N-terminal segment through the anthrax channel. The N-terminal chain is unstructured and leads the permeation process for the LF protein. The simulations were conducted in explicit solvent with milestoning theory, making it possible to extract kinetic information from nanosecond to millisecond time scales. We illustrate that the initial event is strongly influenced by the protonation states of the permeating amino acids. While the N-terminal segment passes easily at high protonation state through the anthrax channel (and the ϕ clamp), the initial permeation represents a critical step, which can be irreversible and establishes a hook in the channel mouth.

Publisher URL: http://dx.doi.org/10.1021/jacs.7b07419

DOI: 10.1021/jacs.7b07419

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