Open AccessThe Impact of Protonation on Early Translocation of Anthrax Lethal Factor: Kinetics from Molecular Dynamics Simulations and Milestoning Theory
Author(s) -
Piao Ma,
Alfredo E. Cárdenas,
Mangesh I. Chaudhari,
Ron Elber,
Susan Rempe
Publication year - 2017
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.7b07419
Subject(s) - protonation , chemistry , permeation , anthrax toxin , molecular dynamics , kinetics , computational chemistry , nanosecond , chemical physics , channel (broadcasting) , organic chemistry , ion , membrane , biochemistry , physics , laser , quantum mechanics , optics , fusion protein , gene , recombinant dna , electrical engineering , engineering
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. 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.