Web interface for brownian dynamics simulation of ion transport and its applications to beta‐barrel pores

Lee, Kyu Il; Jo, Sunhwan; Rui, Huan; Egwolf, Bernhard; Roux, Benoı̂t; Pastor, Richard W.; Im, Wonpil

doi:10.1002/jcc.21952

Cited by 45 publications

(56 citation statements)

References 42 publications

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“…5B) may also be an indication that the charged residues responsible for channel selectivity are not located near one of the channel entrances. This hypothesis is supported by calculations performed by Lee et al [33] showing that the protonation of several histidine residues dramatically changes the electric potential drop, mainly in the bottleneck of the channel (Fig 9 in ref. [33]).…”

Section: Pa 63 Conductance Changes With Solution Phsupporting

confidence: 52%

Effect of the Endosomal Acidification on Small Ion Transport Through the Anthrax Toxin PA63 Channel

Kalu

Alcaraz

Yamini

et al. 2018

Biophysical Journal

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Tight regulation of pH is critical for the structure and function of cells and organelles. The pH environment changes dramatically along the endocytic pathway, an internalization transport process that is 'hijacked' by many intracellularly active bacterial exotoxins, including the anthrax toxin. Here we investigate the role of pH on singlechannel properties of the anthrax toxin channel, PA 63 . Using conductance and current noise analysis, blocker binding, ion selectivity, and PEG partitioning measurements, we show that the channel exists in two different open states ('maximum' and 'main') at pH  5.5, while only a maximum conductance state is detected at pH  5.5. We describe two substantially distinct patterns of PA 63 conductance dependence on KCl concentration uncovered at pH 6.5 and 4.5.

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Section: Pa 63 Conductance Changes With Solution Phsupporting

confidence: 52%

Effect of the Endosomal Acidification on Small Ion Transport Through the Anthrax Toxin PA63 Channel

Kalu

Alcaraz

Yamini

et al. 2018

Biophysical Journal

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“…This box is the same size as that used in the Grand Canonical Monte Carlo/Brownian Dynamics simulations of wt BfrB described previously (28, 39). Both the box and the BfrB molecule were centered at the origin.…”

Section: Methodsmentioning

confidence: 99%

Concerted Motions Networking Pores and Distant Ferroxidase Centers Enable Bacterioferritin Function and Iron Traffic

Yao¹,

Rui²,

Kumar³

et al. 2015

Biochemistry

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X-ray crystallography, molecular dynamics (MD) simulations and biochemistry were utilized to investigate the effect of introducing hydrophobic interactions in the 4-fold (N148L and Q151L) and B-pores (D34F) of Pseudomonas aeruginosa bacterioferritin B (BfrB) on BfrB function. The structures show only local structural perturbations and confirm the anticipated hydrophobic interactions. Surprisingly, structures obtained after soaking crystals in Fe2+-containing crystallization solution revealed that although iron loads into the ferroxidase centers of the mutants, the side chains of ferroxidase ligands E51 and H130 do not reorganize to bind the iron ions, as is seen in the wt BfrB structures. Similar experiments with a double mutant (C89S/K96C) prepared to introduce changes outside the pores show competent ferroxidase centers that function akin to those in wt BfrB. MD simulations comparing wt BfrB with the D34F and N148L mutants show that the mutants exhibit significantly reduced flexibility, and reveal a network of concerted motions linking ferroxidase centers and 4-fold and B-pores, which are important for imparting ferroxidase centers in BfrB with the required flexibility to function efficiently. In agreement, the efficiency of Fe2+ oxidation and uptake of the 4-fold and B-pore mutants in solution is significantly compromised relative to wt or C89S/K96C BfrB. Finally, our structures show a large number of previously unknown iron binding sites in the interior cavity and B-pores of BfrB, which reveal in unprecedented detail conduits followed by iron and phosphate ions across the BfrB shell, as well as paths in the interior cavity that may facilitate nucleation of the iron phosphate mineral.

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“…The equilibrated protein structure was used as an input for BD simulations using the Grand Canonical Monte Carlo/Brownian dynamics (GCMC/BD) simulation software (48). Input files for the GCMC/BD simulations were generated using the CHARMM Graphical User Interface (49). Simulations were carried out with a grid spacing of 0.5 Å and a simulation box with dimensions of 85 × 82 × 102 Å 3 with a 5-Å buffer region.…”

Section: Methodsmentioning

confidence: 99%

“…The diffusion coefficients of K + and Cl − in bulk solution were taken as 0.196 Å 2 /ps and 0.203 Å 2 /ps, respectively (50). The diffusion coefficients corresponding to these ions inside the channel's pore were taken as one-half of their values in bulk using a 10-Å switching function on both ends of the channel to mimic the effect of confinement (49). The dielectric constants of both the membrane and protein regions were set to 2, and that of all aqueous regions was set to 80.…”

Section: Methodsmentioning

confidence: 99%

Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel

Harpole

Grosman

2014

Proc. Natl. Acad. Sci. U.S.A.

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On the basis of single-channel currents recorded from the muscle nicotinic acetylcholine receptor (AChR), we have recently hypothesized that the conformation adopted by the glutamate side chains at the first turn of the pore-lining α-helices is a key determinant of the rate of ion permeation. In this paper, we set out to test these ideas within a framework of atomic detail and stereochemical rigor by conducting all-atom molecular dynamics and Brownian dynamics simulations on an extensively validated model of the open-channel muscle AChR. Our simulations provided ample support to the notion that the different rotamers of these glutamates partition into two classes that differ markedly in their ability to catalyze ion conduction, and that the conformations of the four wild-type glutamates are such that two of them "fall" in each rotamer class. Moreover, the simulations allowed us to identify the mm (χ 1 ≅ -60°; χ 2 ≅ -60°) and tp (χ 1 ≅ 180°; χ 2 ≅ +60°) rotamers as the likely conduction-catalyzing conformations of the AChR's selectivity-filter glutamates. More generally, our work shows an example of how experimental benchmarks can guide molecular simulations into providing a type of structural and mechanistic insight that seems otherwise unattainable.nicotinic receptor | glutamate rotamers T he role an ion channel can play in the physiology of a cell is dictated by the rate at which ions permeate, the type of ions that permeate, the stimulus that gates the channel open, the rates of interconversion among all conductive and nonconductive conformations, and the channel's level of expression in the membrane. In this paper, we are concerned with the chemical determinants of the rate at which cations permeate through the muscle nicotinic acetylcholine receptor (AChR), an archetypal neurotransmitter-gated ion channel.Several "rings" of negatively charged residues decorate the walls of the ion-permeation pathway of the muscle nicotinic AChR. Of these, it is the ring of four glutamates and one glutamine in the first (N-terminal) turn of the pore-lining M2 transmembrane α-helices (the "intermediate ring of charge" at position -1′; Fig. 1A) that lowers the energetic barrier to cation permeation the most (1). Recently, on the basis of single-channel currents recorded from mutant AChRs, we proposed that only two of the four glutamates in the ring contribute to set the size of the unitary currents, and that these glutamates are deprotonated even at pH 6.0 (2). This is in stark contrast with the situation in voltage-dependent Ca 2+ channels (Ca V channels) and cyclicnucleotide-gated channels (CNG channels), for example, where all four selectivity-filter glutamates have been suggested to contribute (directly or indirectly) to the formation of one (in Ca V channels) or two (in CNG channels) proton-binding sites that are largely protonated at pH 6.0 (3, 4). Moreover, our results led us to propose that the difference between the muscle-AChR glutamates that catalyze cation permeation and those that do not is the conformation adopte...

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Web interface for brownian dynamics simulation of ion transport and its applications to beta‐barrel pores

Cited by 45 publications

References 42 publications

Effect of the Endosomal Acidification on Small Ion Transport Through the Anthrax Toxin PA63 Channel

Effect of the Endosomal Acidification on Small Ion Transport Through the Anthrax Toxin PA63 Channel

Concerted Motions Networking Pores and Distant Ferroxidase Centers Enable Bacterioferritin Function and Iron Traffic

Side-chain conformation at the selectivity filter shapes the permeation free-energy landscape of an ion channel

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