Dual Mechanism of Ion Permeation through VDAC Revealed with Inorganic Phosphate Ions and Phosphate Metabolites

Krammer, Eva-Maria; Vu, Giang T. H.; Homblé, Fabrice; Prévost, Martine

doi:10.1371/journal.pone.0121746

Cited by 20 publications

(26 citation statements)

References 78 publications

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“…However, the exact mechanism by which other metabolites are excluded [98] is a subject of further investigations. Recently, Krammer et al [138] reported a detailed application of MD and Adopted-Force Biased MD simulations to VDAC-facilitated transport of metabolites with different charges. The study emphasized the role of clusters of basic residues in the selectivity mechanisms.…”

Section: Unsolved Problems In Vdac Structure and Functionmentioning

confidence: 99%

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

Noskov

Rostovtseva

Chamberlin

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane provides a controlled pathway for respiratory metabolites in and out of the mitochondria. In spite of the wealth of experimental data from structural, biochemical, and biophysical investigations, the exact mechanisms governing selective ion and metabolite transport, especially the role of titratable charged residues and interactions with soluble cytosolic proteins, remain hotly debated in the field. The computational advances hold a promise to provide a much sought-after solution to many of the scientific disputes around solute and ion transport through VDAC and hence, across the mitochondrial outer membrane. In this review, we examine how Molecular Dynamics, Free Energy, and Brownian Dynamics simulations of the large β-barrel channel, VDAC, advanced our understanding. We will provide a short overview of non-conventional techniques and also discuss examples of how the modeling excursions into VDAC biophysics prospectively aid experimental efforts.

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Section: Unsolved Problems In Vdac Structure and Functionmentioning

confidence: 99%

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

Noskov

Rostovtseva

Chamberlin

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…The CG simulations point to two main pore regions which are favorably sampled by the chloride ions. One is located between the N-terminal helix and the extracellular medium and contains Arg15 and Arg218 side chains which have been reported, in several studies to be key partners of ATP during its permeation through VDAC1 (Choudhary et al, 2014;Krammer et al, 2015;Noskov et al, 2013). The other region encompasses the part of the N-terminal helix oriented towards the intermembrane space which contains K12 and K20.…”

Section: Discussionmentioning

confidence: 99%

“…1). Although these structures have been a matter of some debate (Colombini, 2016(Colombini, , 2009Hiller et al, 2010) several electrophysiological data obtained in planar lipid bilayers were reported to corroborate the VDAC structures representing its open state (Choudhary et al, 2014;Hiller et al, 2010;Krammer et al, 2015Krammer et al, , 2014Krammer et al, , 2011Lee et al, 2011;Noskov et al, 2013;Rui et al, 2011;Teijido et al, 2014;Villinger et al, 2010;Weiser et al, 2014;Zachariae et al, 2012).…”

Section: Introductionmentioning

confidence: 95%

“…C i (z) was determined by dividing the simulation box into 1 Å wide slices. This method has been successfully used for the determination of the free energy profile of small compounds inside protein pores (Luo et al, 2010;Wang et al, 2007) and also of ions inside human VDAC1 (Rui et al, 2011) and mVDAC1 (Krammer et al, 2015(Krammer et al, , 2013(Krammer et al, , 2011. Different interactions were monitored in the atomistic and CG MD trajectories.…”

Section: Analysis Of the Trajectoriesmentioning

confidence: 99%

“…In particular, all atom (atomistic) molecular dynamics (MD) and Brownian dynamics (BD) simulations have been used to investigate the mechanism of small inorganic ion and metabolite translocation through VDAC ( Fig. 1) (Choudhary et al, 2010;Krammer et al, 2015Krammer et al, , 2014Krammer et al, , 2013Krammer et al, , 2011Lee et al, 2011;Mlayeh et al, 2017;Rui et al, 2011). They showed that VDAC selectivity towards small inorganic anions is promoted by the distribution of charged residues inside the pore creating, at low salt concentration, a favorable electrostatic potential and that it diminishes with increasing concentration due to a screening of the protein charges (Krammer et al, 2014(Krammer et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Lipid composition and salt concentration as regulatory factors of the anion selectivity of VDAC studied by coarse-grained molecular dynamics simulations

Liefferinge

Krammer

Sengupta

et al. 2019

Chemistry and Physics of Lipids

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The voltage-dependent anion channel (VDAC) is a mitochondrial outer membrane protein whose fundamental function is to facilitate and regulate the flow of metabolites between the cytosol and the mitochondrial intermembrane space. Using coarse-grained molecular dynamics simulations, we investigated the dependence of VDAC selectivity towards small inorganic anions on two factors: the ionic strength and the lipid composition. In agreement with experimental data we found that VDAC becomes less anion selective with increasing salt concentration due to the screening of a few basic residues that point into the pore lumen. The molecular dynamics simulations provide insight into the regulation mechanism of VDAC selectivity by the composition in the lipid membrane and suggest that the ion distribution is differently modulated by POPE compared to the POPC bilayer. This occurs through the more persistent interactions of acidic residues located at both rims of the β-barrel with head groups of POPE which in turn impact the electrostatic potential and thereby the selectivity of the pore. This mechanism occurs not only in POPE single component membranes but also in a mixed POPE/POPC bilayer by an enrichment of POPE over POPC lipids on the surface of VDAC. Thus we show here that computationally-inexpensive coarse-grained simulations are able to capture, in a semi-quantitative way, essential features of VDAC anion selectivity and could pave the way toward a molecular level understanding of metabolite transport in natural membranes.

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Plant VDAC Permeability: Molecular Basis and Role in Oxidative Stress

Homblé¹,

Kmita²,

Saidani³

et al. 2017

Molecular Basis for Mitochondrial Signaling

Self Cite

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The mitochondrial voltage-dependent anion-selective channel (VDAC) is highly abundant in the mitochondrial outer membrane. It is permeable to molecules with a size up to about 5kDa and is the main pathway for the exchange of metabolites and ions between the mitochondrial intermembrane space and the cytosol. Experimental studies performed for plant VDAC have shown that the channel displays properties reported for VDACs of other eukaryotic organisms. Firstly, it transports compounds as diverse as inorganic ions (e.g., K + and Cl -), adenylates (e.g., ATP and AMP) and large macromolecules (tRNA and DNA). Secondly, despite its wide pore, the channel displays selectivity towards these compounds, i.e. it distinguishes between K + and Clbut also between ATP and AMP. The question of how VDAC can selectively transport these different compounds is addressed in this chapter based on data obtained for plant VDAC. It is well known that all organisms have at least one canonical VDAC isoform that shares similar electrophysiological properties and secondary structure with cognate VDAC of other organisms. For instance, this is the case of the mammalian VDAC1, the yeast Saccharomyces cerevisiae VDAC1 and the PcVDAC purified from the bean Phaseolus coccineus seeds. Consequently, Brownian dynamic simulations of monatomic ion permeation through the experimental threedimensional structure of the mammalian VDAC1 and the PcVDAC modeled structure predict fairly well conductance and selectivity of both the proteins. In addition, the data of molecular simulation studies performed on the mammalian VDAC1 agree with the experimental data obtained for PcVDAC, which suggests a similar permeation process for these VDAC proteins. Accordingly, both the experimental and theoretical studies indicate that the selectivity for inorganic ions is a consequence of the excess of positive charges and their distribution inside the pore and the absence of defined pathways for the permeation. In contrast, the permeation of metabolites involves a major binding site located at the N-terminal helix which folded into the pore lumen and occurs through a preferential pathway. The key residues forming the binding site are conserved in the PcVDAC pointing to the conserved permeation process. The process might be affected by VDAC-interaction with other proteins. For example, it is suggested that plant VDAC is involved in the oxidative stress response which includes cytosolic hexokinase and thioredoxin binding to VDAC. This in turn may influence the exchange of molecules between mitochondria and the cytosol.

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Dual Mechanism of Ion Permeation through VDAC Revealed with Inorganic Phosphate Ions and Phosphate Metabolites

Cited by 20 publications

References 78 publications

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

Current state of theoretical and experimental studies of the voltage-dependent anion channel (VDAC)

Lipid composition and salt concentration as regulatory factors of the anion selectivity of VDAC studied by coarse-grained molecular dynamics simulations

Plant VDAC Permeability: Molecular Basis and Role in Oxidative Stress

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