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

Abstract

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. Here, 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.

Authors:
 [1];  [2];  [3]; ORCiD logo [4]; ORCiD logo [3]
  1. Univ. of Texas, Austin, TX (United States). Dept. of Chemistry
  2. Univ. of Texas, Austin, TX (United States). Inst. for Computational Engineering and Sciences
  3. Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Biological and Engineering Sciences
  4. Univ. of Texas, Austin, TX (United States). Dept. of Chemistry; Univ. of Texas, Austin, TX (United States). Inst. for Computational Engineering and Sciences
Publication Date:
Research Org.:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)
OSTI Identifier:
1474052
Report Number(s):
[SAND-2018-10162J]
[Journal ID: ISSN 0002-7863; 667922]
Grant/Contract Number:  
[AC04-94AL85000; NA0003525; AC52-06NA25396]
Resource Type:
Accepted Manuscript
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
[ Journal Volume: 139; Journal Issue: 42]; Journal ID: ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Ma, Piao, Cardenas, Alfredo E., Chaudhari, Mangesh I., Elber, Ron, and Rempe, Susan B. The Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory. United States: N. p., 2017. Web. doi:10.1021/jacs.7b07419.
Ma, Piao, Cardenas, Alfredo E., Chaudhari, Mangesh I., Elber, Ron, & Rempe, Susan B. The Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory. United States. doi:10.1021/jacs.7b07419.
Ma, Piao, Cardenas, Alfredo E., Chaudhari, Mangesh I., Elber, Ron, and Rempe, Susan B. Wed . "The Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory". United States. doi:10.1021/jacs.7b07419. https://www.osti.gov/servlets/purl/1474052.
@article{osti_1474052,
title = {The Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory},
author = {Ma, Piao and Cardenas, Alfredo E. and Chaudhari, Mangesh I. and Elber, Ron and Rempe, Susan B.},
abstractNote = {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. Here, 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.},
doi = {10.1021/jacs.7b07419},
journal = {Journal of the American Chemical Society},
number = [42],
volume = [139],
place = {United States},
year = {2017},
month = {10}
}

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