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

Journal Article · · Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
 [1];  [1];  [2];  [1];  [2]
  1. Univ. of Texas, Austin, TX (United States)
  2. Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
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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.
Research Organization:
Sandia National Laboratories (SNL-NM), Albuquerque, NM (United States)
Sponsoring Organization:
Joint Science and Technology Office for Chemical and Biological Defense; USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division
Grant/Contract Number:
AC04-94AL85000; AC52-06NA25396; NA0003525
OSTI ID:
1526909
Report Number(s):
SAND--2019-6581J; 676313
Journal Information:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry, Journal Name: Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry Journal Issue: 45 Vol. 122; ISSN 1520-6106
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (1)

Kinetics and Free Energy of Ligand Dissociation Using Weighted Ensemble Milestoning text January 2020

Figures / Tables (10)

Fig. 1(p. 4)figure Fig. 1
Table 1(p. 5)table Table 1
Fig. 2(p. 10)figure Fig. 2
Fig. 3(p. 12)figure Fig. 3
Fig. 4(p. 13)figure Fig. 4
Fig. 5(p. 14)figure Fig. 5
Figure 6(p. 15)figure Figure 6
Fig. 7(p. 16)figure Fig. 7
Fig. 8(p. 17)figure Fig. 8
Fig. 9(p. 18)figure Fig. 9

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