Open AccessProbing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning
Author(s) -
Piao Ma,
Alfredo E. Cárdenas,
Mangesh I. Chaudhari,
Ron Elber,
Susan Rempe
Publication year - 2018
Publication title -
the journal of physical chemistry. b
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.864
H-Index - 392
eISSN - 1520-6106
pISSN - 1520-5207
DOI - 10.1021/acs.jpcb.8b08304
Subject(s) - chromosomal translocation , anthrax toxin , mutant , cytosol , endosome , biophysics , channel (broadcasting) , static electricity , physics , chemistry , biology , microbiology and biotechnology , computer science , fusion protein , biochemistry , gene , intracellular , enzyme , computer network , quantum mechanics , recombinant dna
Anthrax toxin consists of a cation channel and two protein factors. Translocation of the anthrax protein factors from endosomal to the cytosolic compartment is a complex process which utilizes the cation channel. An atomically detailed understanding of the function of the anthrax translocation machinery is incomplete. We report atomically detailed simulations of the lethal factor and channel mutants. Kinetic and thermodynamic properties of early events in the translocation process are computed within the Milestoning theory and algorithm. Several mutants of the channel illustrate that long-range electrostatic interactions provide the dominant driving force for translocation. No external energy input is required because the lower pH in the endosome relative to the cytosol drives the initial translocation process forward. Channel mutants with variable sizes cause smaller effects on translocation events relative to charge manipulations. Comparison with available experimental data is provided.