biostudies-literatureMa PNIGMS NIH HHS10296-10305https://www.ebi.ac.uk/biostudies/studies/S-EPMC6289263biostudies-literatureUnknown122(45)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.The journal of physical chemistry. BProbing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning.PMC6289263R01 GM059796R01 GM085062Ma PElber RCardenas AEChaudhari MIRempe SBfalseProbing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning.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.2018-01-01T00:00:00Z2018 Nov2021-02-19T21:53:50Z2020-05-21T18:49:46ZS-EPMC62892633033868910.1021/acs.jpcb.8b08304