Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
AbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainstric coefficient Ep. Selectivity arises from the balance of electrostatic forces and steric repulsion by excluded volume of ions and sidechains of the channel protein in the highly concentrated and charged (~30 M) selectivity filter resembling an ionic liquid. Ions and structural side-chains are des Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainscribed as mobile charged hard spheres that assume positions of minimal free energy. Water is a dielectric continuum. Size selectivity (ratio of Na* ocSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
cupancy to K* occupancy) and charge selectivity (Na* to Ca2*) are computed in 10’5 M Ca2*. In general, small R reduces ion occupancy and favors Na* ovAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainse. Size selectivity depends on R and is independent of Epi charge selectivity depends on both R and Ep. Thus, small R and Ep make an efficient Na channel that excludes K* and Ca2* while maximizing Na* occupancy. Selectivity properties depend on interactions that cannot be described by qualitative or Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains verbal models or by quantitative models with a fixed free energy landscape.Keywords: Monte Carlo, Simulations, DEKA, Na channel, Ca channel, electrosSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
taticssteríc Na' SelectivityBoơa et alIntroductionThe selectivity of nerve membranes for Na* allows nerve cells (0 conduct action potentials and has bAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainss like Nd plays a crucial role in selectivity (in enzymes (3,4) and channels (5)) and thus the molecular and atomic-basis of Na selective binding (6,7) is a biological problem of great importance. indeed, in a functional and historical sense channels—then called ‘conductances’—were defined by their Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsselectivity, transport, and binding properties before Mullins suggested that channels were pores in membranes (8,9) and Narahashi (10,11) suggested poSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
res were in channel proteins at different locations in die membrane (10-12). rhe atomic (‘tertiary’) structure of die channel protein is of great impoAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsg from the structure of the protein itself. Unfortunately, the structures of Na and Ca channels are not known.It is natural (5) to imagine that selective binding arises from ‘chemical’ effects involving some type of specific localized chemical bond between a Na' ion and binding site of the channel p Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsrotein but it is difficult to convert this natural idea into a physical model that reproduces the binding of a channel as measured over a range of conSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
centrations of many ions. Computations of properties over a range of conditions are needed to compare models of selectivity widi experimental measuremAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains another.Predicting macroscopic channel function from properties of a chemical bond is difficult because the prediction involves quantum mechanics of a solvated ion in an inhomogeneous system that couples atomic scales of the chemical bond to macroscopic scales of the electrochemical potential. The Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsmacroscopic scale is unavoidable because the natural function of the Na channel is to change the transmembrane potential, a macroscopic quantity. TheSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
natural function of Ca channels and many other channels is to change the concentration of ions, another macroscopic quantity. Discussions and models oAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains a model that reaches from atomic scales of femtoseconds and Angstroms to macroscopic scales of msec and micrometers while simulating chemical bonds and number densities (‘concentrations’) of micromolar is a challenge that cannot be met with present technology, in our view. Nor is it clear how a mod Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsel with so much detail would yield insight. We choose to consider a simpler model. When simpler reduced models using only physical variables explain bSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
iological data and (unction with a (ew adjustable parameters, they are OÍ considerable help in understanding the system well enough, lor example, to bAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsothesis that other more chemical effects were not selected by evolution Io perform that (unction.We choose to compute physical effects first because we think we (more or less) knowhow to do this, building on the large literature describing ionic solutions in general (13-22). In our reduced model, se Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainslective piopeitics arc outputs of the model that arise from the balance between electrostatic and steric forces in the confined space of a channel. OuSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
r model includes the same electrostatic and steric specific (i.e., ‘selective’) properties that characterize the free energy1M&2022 1131:18 AMp.2Boơa AbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsement produced by the channel protein to make a reduced description of the structure of the channel.We show here how Na* selectivity can arise (at equilibrium) using a reduced model in a pore that only detects the radius and charge of ions (24,25). This pore balances steric effects of ionic excluded Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains volume against electrostatic effects of ionic charge and uses polarization charges at the dielectric boundary (between protein and pore) to ‘amplify’Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
the electrostatic effects. Selectivity arises from the steric competition for space (26,27) between mobile ions like Na* and structural ions, amino aAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsiquid (28,29) more than an electrolyte solution. The competition between space and charge gives the acronym CSC (charge/space competition) (24-27,30-48). CSC is closely related to models used to compute the free energy of binding of K* in the K channel (49-51).Reduced models of this type have dealt Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsquantitatively with many properties of several types of channels including the ryanodine receptor RyR and OmpF porin (24-27,30-50). In RyR such modelsSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
successfully predicted an anomalous mole fraction effect before it was measured (30,52,53). These models also explain RyR mutations that reduce the sAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsls (49-51). Similar models produced a successful plan for the conversion of a nonselective bacterial channel OmpF porin into a decent Ca channel (43,55-57). In particular, Vrouneraets, er al, (57) verified one of the important features of the CSC mechanism by showing that decreasing pore volume incr Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainseases selectivity.Our approach is quantitative in that it reproduces the actual binding curves reported in physiological experiments over a range of cSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
oncentrations and in mixtures of ions (6,54.58-62); it is distinct from verbal models popular in structural biology (5,63-66) or simulations with largAbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainselectivity without presenting binding curves are hard to deal with. It is difficult to distinguish one model from another if they do not reproduce binding curves measured in experiments.We use Monte Carlo MC simulations developed originally for bulk fluids (67,68) and then extended to include some o Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsf the inhomogeneities introduced by the channel protein. The simulations include (l)the energies of the electric field produced by the very large densSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
ity of side chains (i.e., structural charges) of the channel protein, some 30 M in these proteins (see Methods: Channel Model); (2) the energies that AbstractMonte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielect Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainse of ions, side chains, and the rest of the channel protein) that balance the electrostatic forces that crowd spherical ions to these densities. We invoke only the forces and energies present in macroscopic electrolyte solutions and likely to be present in channels (24,25,36,37,40,48,69-82). These f Steric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chainsorces and energies are used to describe the distinctive properties of the channel environment. The narrow space of the channel is produced by the exclSteric Selectivity in Na Channels Arising from Protein Polarization and Mobile Side Chains
uded volume of the protein and its side chains. The dielectric environment of the protein is included in the model. The electrostatic field is computeGọi ngay
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