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

Ma, Piao; Cardenas, Alfredo E.; Chaudhari, Mangesh I.; Elber, Ron; Rempe, Susan B.

doi:10.1021/jacs.7b07419

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

Journal Article · Wed Oct 11 00:00:00 EDT 2017 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.7b07419· OSTI ID:1474052

Ma, Piao ^[1]; Cardenas, Alfredo E. ^[2]; Chaudhari, Mangesh I. ^[3];

^[4];

^[3]

Univ. of Texas, Austin, TX (United States). Dept. of Chemistry
Univ. of Texas, Austin, TX (United States). Inst. for Computational Engineering and Sciences
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Biological and Engineering Sciences
Univ. of Texas, Austin, TX (United States). Dept. of Chemistry; Univ. of Texas, Austin, TX (United States). Inst. for Computational Engineering and Sciences

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.

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Research Organization:: Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)

Grant/Contract Number:: AC04-94AL85000; NA0003525; AC52-06NA25396

OSTI ID:: 1474052

Report Number(s):: SAND-2018-10162J; 667922

Journal Information:: Journal of the American Chemical Society, Vol. 139, Issue 42; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 23 works

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References (24)

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