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Title: Probing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning

Abstract

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 introduce 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 needed 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.

Authors:
 [1];  [1];  [2]; ORCiD logo [1]; ORCiD logo [2]
  1. Univ. of Texas, Austin, TX (United States)
  2. Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Publication Date:
Research Org.:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division; Joint Science and Technology Office for Chemical and Biological Defense
OSTI Identifier:
1526909
Report Number(s):
SAND-2019-6581J
Journal ID: ISSN 1520-6106; 676313
Grant/Contract Number:  
AC04-94AL85000; NA0003525; AC52-06NA25396; DTRTA10027IA-3167; GM59796; F1896
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
Additional Journal Information:
Journal Volume: 122; Journal Issue: 45; Journal ID: ISSN 1520-6106
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English

Citation Formats

Ma, Piao, Cardenas, Alfredo E., Chaudhari, Mangesh I., Elber, Ron, and Rempe, Susan B. Probing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning. United States: N. p., 2018. Web. doi:10.1021/acs.jpcb.8b08304.
Ma, Piao, Cardenas, Alfredo E., Chaudhari, Mangesh I., Elber, Ron, & Rempe, Susan B. Probing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning. United States. doi:10.1021/acs.jpcb.8b08304.
Ma, Piao, Cardenas, Alfredo E., Chaudhari, Mangesh I., Elber, Ron, and Rempe, Susan B. Fri . "Probing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning". United States. doi:10.1021/acs.jpcb.8b08304. https://www.osti.gov/servlets/purl/1526909.
@article{osti_1526909,
title = {Probing Translocation in Mutants of the Anthrax Channel: Atomically Detailed Simulations with Milestoning},
author = {Ma, Piao and Cardenas, Alfredo E. and Chaudhari, Mangesh I. and Elber, Ron and Rempe, Susan B.},
abstractNote = {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 introduce 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 needed 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.},
doi = {10.1021/acs.jpcb.8b08304},
journal = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},
number = 45,
volume = 122,
place = {United States},
year = {2018},
month = {10}
}

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