Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains

Boda, Dezső; Nonner, Wolfgang; Valiskó, Mónika; Henderson, Douglas; Eisenberg, Robert S.; Gillespie, Dirk

doi:10.1529/biophysj.107.105478

Cited by 130 publications

(205 citation statements)

References 175 publications

(342 reference statements)

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“…Hence, OprP does not share the free energy landscape of permeation with ''typical'' channels or pores but it rather resembles a protein with a binding site with two openings that bridge the outer membrane. OprP can be understood as a brush-like nanopore, in which charged side chains provide a high local concentration of counter charge to stabilize a charged substrate, similar to highly simplified but successful models of sodium and calcium channels (23). In addition, it uses differential desolvation to probe different anions and can so discriminate between a chloride ion that ''hides'' under its hydration shell and a larger phosphate ion whose size forces it to make direct contact with the sensing charged brushes.…”

Section: Discussionmentioning

confidence: 99%

Simulations of anion transport through OprP reveal the molecular basis for high affinity and selectivity for phosphate

Pongprayoon

Beckstein

Wee

et al. 2009

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

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The outer membrane protein OprP from Pseudomonas aeruginosa forms a phosphate selective pore. To understand the mechanism of phosphate permeation and selectivity, we used three simulation techniques [equilibrium molecular dynamics simulations, steered molecular dynamics, and calculation of a potential of mean force (PMF)]. The PMF for phosphate reveals a deep free energy well midway along the OprP channel. Two adjacent phosphate-binding sites (W1 and W2), each with a well depth of Ϸ8 kT, are identified close to the L3 loop in the most constricted region of the pore. A dissociation constant for phosphate of 6 M is computed from the PMF, within the range of reported experimental values. The transfer of phosphate between sites W1 and W2 is correlated with changes in conformation of the sidechain of K121, which serves as a ''charged brush'' to facilitate phosphate passage between the two subsites. OprP also binds chloride, but less strongly than phosphate, as calculated from a Cl ؊ PMF. The difference in affinity and hence selectivity is due to the ''Lys-cluster'' motif, the positive charges of which interact strongly with a partially dehydrated phosphate ion but are shielded from a Cl ؊ by the hydration shell of the smaller ion. Our simulations suggest that OprP does not conform to the conventional picture of a channel with relatively flat energy landscape for permeant ions, but rather resembles a membrane-inserted binding protein with a high specificity that allows access to a centrally located binding site from both the extracellular and the periplasmic spaces.free energy profile ͉ potential of mean force ͉ anion selectivity ͉ hydration ͉ molecular dynamics simulation

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Section: Discussionmentioning

confidence: 99%

Simulations of anion transport through OprP reveal the molecular basis for high affinity and selectivity for phosphate

Pongprayoon

Beckstein

Wee

et al. 2009

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

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“…We introduce the repulsion energy of solid spheres. 14,15,17,19,[49][50][51][52] In this way, the variational calculus extends the primitive model to spatially complex, nonequilibrium time dependent situations, creating a field theory of ionic solutions.…”

Section: Introductionmentioning

confidence: 99%

Energy variational analysis of ions in water and channels: Field theory for primitive models of complex ionic fluids

Eisenberg

Hyon

2010

The Journal of Chemical Physics

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Ionic solutions are mixtures of interacting anions and cations. They hardly resemble dilute gases of uncharged noninteracting point particles described in elementary textbooks. Biological and electrochemical solutions have many components that interact strongly as they flow in concentrated environments near electrodes, ion channels, or active sites of enzymes. Interactions in concentrated environments help determine the characteristic properties of electrodes, enzymes, and ion channels. Flows are driven by a combination of electrical and chemical potentials that depend on the charges, concentrations, and sizes of all ions, not just the same type of ion. We use a variational method EnVarA (energy variational analysis) that combines Hamilton's least action and Rayleigh's dissipation principles to create a variational field theory that includes flow, friction, and complex structure with physical boundary conditions. EnVarA optimizes both the action integral functional of classical mechanics and the dissipation functional. These functionals can include entropy and dissipation as well as potential energy. The stationary point of the action is determined with respect to the trajectory of particles. The stationary point of the dissipation is determined with respect to rate functions (such as velocity). Both variations are written in one Eulerian (laboratory) framework. In variational analysis, an "extra layer" of mathematics is used to derive partial differential equations. Energies and dissipations of different components are combined in EnVarA and Euler-Lagrange equations are then derived. These partial differential equations are the unique consequence of the contributions of individual components. The form and parameters of the partial differential equations are determined by algebra without additional physical content or assumptions. The partial differential equations of mixtures automatically combine physical properties of individual (unmixed) components. If a new component is added to the energy or dissipation, the Euler-Lagrange equations change form and interaction terms appear without additional adjustable parameters. EnVarA has previously been used to compute properties of liquid crystals, polymer fluids, and electrorheological fluids containing solid balls and charged oil droplets that fission and fuse. Here we apply EnVarA to the primitive model of electrolytes in which ions are spheres in a frictional dielectric. The resulting Euler-Lagrange equations include electrostatics and diffusion and friction. They are a time dependent generalization of the Poisson-Nernst-Planck equations of semiconductors, electrochemistry, and molecular biophysics. They include the finite diameter of ions. The EnVarA treatment is applied to ions next to a charged wall, where layering is observed. Applied to an ion channel, EnVarA calculates a quick transient pile-up of electric charge, transient and steady flow through the channel, stationary "binding" in the channel, and the eventual accumulation of salts in "unstirred layers" ne...

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“…ELIC, a bacterial pentemeric ligand-gated ion channel, is cation selective and has a ring of five anionic glutamate (E) side chains (9). Rings of anionic side chains have also been suggested to play a key role in the ion selectivity of voltagegated calcium (Cav) and sodium (Nav) channels (10)(11)(12). Thus, Cav (and some Nav) channels have four anionic residues in a ring (an EEEE motif, where E is the amino acid glutamate).…”

mentioning

confidence: 99%

Designing biomimetic pores based on carbon nanotubes

García‐Fandiño

Sansom

2012

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

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Biomimetic nanopores based on membrane-spanning singlewalled carbon nanotubes have been designed to include selectivity filters based on combinations of anionic and cationic groups mimicking those present in bacterial porins and in voltage-gated sodium and calcium channels. The ion permeation and selectivity properties of these nanopores when embedded in a phospholipid bilayer have been explored by molecular dynamics simulations and free energy profile calculations. The interactions of the nanopores with sodium, potassium, calcium, and chloride ions have been explored as a function of the number of anionic and cationic groups within the selectivity filter. Unbiased molecular dynamics simulations show that the overall selectivity is largely determined by the net charge of the filter. Analysis of distribution functions reveals considerable structuring of the distribution of ions and water within the nanopores. The distributions of ions along the pore axis reveal local selectivity for cations around filter, even in those nanopores (C0) where the net filter charge is zero. Single ion free energy profiles also reveal clear evidence for cation selectivity, even in the C0 nanopores. Detailed analysis of the interactions of the C0 nanopore with Ca 2þ ions reveals that local interactions with the anionic (carboxylate) groups of the selectivity filter lead to (partial) replacement of solvating water as the ion passes through the pore. These studies suggest that a computational biomimetic approach can be used to evaluate our understanding of the design principles of nanopores and channels.

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Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains

Cited by 130 publications

References 175 publications

Simulations of anion transport through OprP reveal the molecular basis for high affinity and selectivity for phosphate

Simulations of anion transport through OprP reveal the molecular basis for high affinity and selectivity for phosphate

Energy variational analysis of ions in water and channels: Field theory for primitive models of complex ionic fluids

Designing biomimetic pores based on carbon nanotubes

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