Bulletin of the American Physical Society
2006 APS March Meeting
Monday–Friday, March 13–17, 2006; Baltimore, MD
Session N29: Focus Session: Physical Models of Ion Channel Function |
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Sponsoring Units: DBP Chair: Bob Eisenberg, Rush University Room: Baltimore Convention Center 326 |
Wednesday, March 15, 2006 8:00AM - 8:12AM |
N29.00001: The metabolic energy cost of action potential velocity Patrick Crotty, Thomas Sangrey, William Levy Voltage changes in neurons and other active cells are caused by the passage of ions across the cell membrane. These ionic currents depend on the transmembrane ion concentration gradients, which in unmyelinated axons are maintained during rest and restored after electrical activity by an ATPase sodium-potassium exchanger in the membrane. The amount of ATP consumed by this exchanger can be taken as the metabolic energy cost of any electrical activity in the axon. We use this measure, along with biophysical models of voltage-gated sodium and potassium ion channels, to quantify the energy cost of action potentials propagating in squid giant axons. We find that the energy of an action potential can be naturally divided into three separate components associated with different aspects of the action potential. We calculate these energy components as functions of the ion channel densities and axon diameters and find that the component associated with the rising phase and velocity of the action potential achieves a minimum near the biological values of these parameters. This result, which is robust with respect to other parameters such as temperature, suggests that evolution has optimized the axon for the energy of the action potential wavefront. [Preview Abstract] |
Wednesday, March 15, 2006 8:12AM - 8:24AM |
N29.00002: The Dependence of Ionic Conduction on the Dielectric Properties of Ion Channels Marco Saraniti, David Marreiro, Shela Aboud The ion channel OmpF porin is a water filled trimer found in the outer membrane of \textit{Escherichia coli}. Each monomer is a hollow barrel structure with a physical constriction near the center that reduces the width of the pore to approximately 6 {\AA}. Highly charged residues line the inside of the pore constriction, generating an intense electric field that facilitates the dynamics of ions through the channel. The cost of simulating these systems for long times is an oversimplification of key physical features of the ion channel system, most notably, the polarization effects related to the solvent (water) and the protein are poorly represented by a stepwise constant dielectric constant. While the use of this model for the aqueous solution inside the permeation pore is arguably suitable because the ionic hydration shell remains intact (at least away from the central constriction), its validity is questionable when used to describe the polarization response of the protein. In this work, a previously validated P$^{3}$M force-field scheme, self-consistently coupled to a Brownian Dynamics kernel, is used to investigate the influence of the protein dielectric constant on permeation in OmpF porin. The computed channel conductivity is in agreement with experimental measurements. Increased cation selectivity at low ionic concentrations is also observed in the simulations and appears to be dependent on the rings of aspartic acid residues around the mouths of the porin. [Preview Abstract] |
Wednesday, March 15, 2006 8:24AM - 8:36AM |
N29.00003: Rocking and Flashing Ratchet Mechanisms of Ion Current Rectification in Asymmetric Nanopores in the Presence of Calcium Zuzanna Siwy, Matthew Powell, Eric Kalman, Bob Eisenberg We have investigated an engineered system of a single nanopore in a plastic membrane that shows rectification depending on the chemical composition of the surrounding solutions. No lipid bilayer is involved so the system is simple and robust with $>$10 gigohm leak resistance. The single nanopores are tapered cones with openings of diameter $\sim $~600 nm and $\sim $~5 nm. The single nanopores were prepared by the track-etching technique. The walls of the pores have carboxylate groups with surface density $\approx $1.5~(\textbf{\textit{e}}/[nm]$^{2})$. Transport properties of these nanopores were studied by recording current-voltage curves in a variety of solutions. In KCl solutions these single asymmetric nanopores are cation selective and rectify with a ratio of limiting conductances $\approx $~4-10. The K ions flow with lower resistance from the smaller to larger opening. Adding millimolar Ca to both sides reverses the direction of rectification and produces a negative incremental resistance; i.e., larger magnitudes of voltage produce smaller magnitudes of ion current. The rectifying properties of these asymmetric nanopores are described by rocking and flashing ratchet models of directional motion. It will be interesting to compare permeation, selectivity, and gating properties of the polymer nanopores and biological voltage-gated calcium channels. [Preview Abstract] |
Wednesday, March 15, 2006 8:36AM - 9:12AM |
N29.00004: Ion selectivity in the ryanodine receptor and other calcium channels. Invited Speaker: Biological ion channels passively conduct ions across cell membranes, some with great specificity. Calcium channels are selective channels that range in their Ca$^{2+}$ affinity depending on the channel's physiological role. For example, the L-type calcium channel has micromolar affinity while the ryanodine receptor (RyR) has millimolar affinity. On the other hand, both of these channels have the chemically-similar EEEE and DDDD amino acid motifs in their selectivity filters. An electrodiffusion model of RyR that reproduces and predicts $>$50 data curves will be presented. In this model, ions are charged, hard spheres and the chemical potential is computed using density functional theory of fluids. Ion selectivity arises from a competition between the need for cations to screen the negative charges of the channel and the crowding of ions in the tiny space of the channel. Charge/space competition implies that selectivity increases as the channel volume decreases (thereby increasing the protein charge density), something that has recently been experimentally confirmed in mutant channels. Dielectric properties can also increase selectivity. In Monte Carlo simulations, Ca$^{2+}$ affinity is much higher when the channel protein has a low dielectric constant. This counterintuitive result occurs because calcium channel selectivity filters are lined with negatively-charged (acidic) amino acids (EEEE or DDDD). These permanent negative charges induce negative polarization charge at the protein/lumen interface. The total negative charge of the protein (polarization plus permanent) is increased, resulting in increased ion densities, increased charge/space competition, and there in increased Ca$^{2+}$ affinity. If no negative protein charges were present, cations would induce enough positive polarization charge to prevent flux. [Preview Abstract] |
Wednesday, March 15, 2006 9:12AM - 9:24AM |
N29.00005: Modeling Activity: Ions to Hydrophobics in Crowded Biological Solutions Montgomery Pettitt Nonideal solutions play a role in many aspects of chemistry. As concentrations increase, concentration itself becomes a less useful quantity to understand equilibria. Industrial and medicinal chemistry often fail due to the difference between concentration and activity. An understanding of the impact of the crowded conditions in the cytoplasm on its biomolecules is of clear importance to biochemical, medical and pharmaceutical science. Work on the use of small biochemical compounds to crowd protein solutions indicates that a quantitative description of their non-ideal behavior is possible and straightforward. Here, we will show what the structural origin of this non-ideal solution behavior is from expression derived from a semi grand ensemble approach. We discuss the consequences of these findings regarding protein folding stability and solvation in crowded solutions through a structural analysis of the m-value or the change in free energy difference of a macromolecule in solution with respect to the concentration of a third component. [Preview Abstract] |
Wednesday, March 15, 2006 9:24AM - 9:36AM |
N29.00006: Entropy driven insulator-metal crossover in ion channels and water filled nanopores Jingshan Zhang, Alex Kamenev, Boris Shklovskii, Anatony Larkin We consider ion transport of an ion channel in a lipid membrane or a water filled nanopore in silicon films [1]. It is known that due to the large ratio of dielectric constants of water (80) and lipid (2), the electric lines of an ion in the channel are squeezed. This should lead to a large electrostatic self-energy barrier for Ohmic resistance [2]. Nevertheless biological channels are well transparent at least for some selected ions. To address this paradox, we study reduction of the electrostatic barrier by a finite concentration of salt in water and/or by immobile charges on the internal channel walls. We show that both types of charges reduce the barrier, leading to insulator-metal crossover resembling metal-insulator transition in excited gas or in doped semiconductors. But here entropy plays the role of quantum mechanics. Evolution of ion channels took into account biological concentration of monovalent salt, and more importantly, made some channels charged from inside to reduce electrostatic barrier for a given sign of ions (cation/anion selectivity). We also show that in the channel with negative wall charges fractionalization of divalent Ca ions into monovalent excitations leads to good Ca-Vs.-Na selectivity of Ca channels. [1] A. Kamenev, J. Zhang, A. I. Larkin, B. I. Shklovskii, Physica A 359, 129 (2006); J. Zhang, A. Kamenev, B. I. Shklovskii, Phys. Rev. Lett. 95, 148101 (2005); cond-mat/0510327. [2] A. Parsegian, Nature 221, 844 (1969). [Preview Abstract] |
Wednesday, March 15, 2006 9:36AM - 9:48AM |
N29.00007: Measurement of gating forces of mechanosensitive channels of large conductance in \textit{Escherichia coli} Elvis Pandzic, Paul Wiseman, Maria Kilfoil In order to sense and respond to external mechanical stimuli, cells have evolved schemes to incorporate mechanosensors within their plasma membranes. Mechanosensitive channels of large conductance (MscL) are used by bacterial cells to respond quickly and effectively to hypo-osmotic shock: the opening of this channel permits cells to quickly release large amounts of osmolytes in order to quickly equalize unbalanced osmotic pressure across a membrane. In this study, we are investigating the physical mechanism of the MscL gating within the native environment of the \textit{Escherichia coli }cells. We are using the green fluorescent protein (GFP) and derivative proteins (CFP, BFP) to label the C-termini of MscL subunits in order to observe the channels in live bacteria by fluorescence microscopy. Moreover, we label the opposite termini with a different chromophore system that constitutes an excellent fluorescence resonance energy transfer (FRET) pair with CFP. Channels are activated within the bacterial membrane by osmotic stress and interactions between differently labeled subunits are measured by fluorescence microscopy. [Preview Abstract] |
Wednesday, March 15, 2006 9:48AM - 10:24AM |
N29.00008: Calculating Ion Permeation through Biological Channel Proteins Invited Speaker: We have developed methodology to simulate the current of ions (Na+, Cl-, etc.) through a general three-dimensional ion channel structure embedded in a lipid bilayer when an electric potential is applied across the membrane. These calculations are done at the level of Brownian dynamics, i.e., ions are treated as particles and their motion is computed using a stochastic algorithm which simulates Brownian motion. Water solvent is treated as a dielectric continuum, which both supplies the thermal agitation underlying the motion of the ions and influences the electrostatic forces on these ions by virtue of its dielectric constant (which differs substantially from that of the protein-membrane complex). Application is made to the Glycine Receptor channel, emphasizing physico-chemical influences on ion current, e.g., charges of critical pore-lining amino acids, channel geometry, etc. [Preview Abstract] |
Wednesday, March 15, 2006 10:24AM - 10:36AM |
N29.00009: Morphometric approach to selectivity and gating of ion channels Roland Roth A physical understanding of selectivity and gating of ion channels requires the free energy of the fluid confined in the channel pore. The free energy depends not only on fluid properties like its density, but also on the interaction between fluid particles and the confining protein, which gives rise to a potentially complicated dependence of the free energy on the conformation of the protein. Here we propose a simple thermodynamic approach that employs the idea that the free energy can be separated into geometrical measures and corresponding thermodynamic coefficients. Our approach enables us to calculate the change in the free energy caused by a change of the pore conformation such as that underlying the gating of an ion channel. We study the connection between the geometrical change of a hydrophobic pore and capillary evaporation, i.e. the effect that water is expelled from the permeation pathway and ion flow is thereby stopped although the pore remains wider than the water or ion diameters. We estimate the energy it takes to remove the water from the pore. Within the same thermodynamic framework, we can also study effects of pore conformation on the equilibrium absorption of ions and thus on ionic selectivity of the channel. [Preview Abstract] |
Wednesday, March 15, 2006 10:36AM - 10:48AM |
N29.00010: Voltage Sensor in Voltage-gated ion channels Francisco Bezanilla Voltage-gated ion channels are intrinsic membrane proteins that play a fundamental role in the generation and propagation of the nerve impulse. Their salient characteristic is that the probability of the ion channel of being open depends steeply on the voltage across the membrane where those channels are inserted. Thus, in a membrane containing many channels, the ionic conductance is controlled by the membrane potential. The voltage exerts its control on the channel by reorienting intrinsic charges in the protein, generally arginine or lysine residues located in the 4th transmembrane segment of the channel protein, a region that has been called the voltage sensor. Upon changing the membrane potential, the charged groups reorient in the field generating a transient current (gating current). The properties of the gating current may be studied with a small number of channels to infer the operation of the sensor at the single molecule level by noise analysis or with a large number of channels to infer the details of the energy landscape the sensor traverses in opening the pore. This information is global in nature and cannot pinpoint the exact origin of the charge movement that generates the gating current. The movement of physical charges in the protein has been inferred with site-directed mutagenesis of the charged residues to histidine that allows the study of proton accessibility. The actual movement has been studied with fluorescence spectroscopy, fluorescence resonance energy transfer. The combined information of site-directed mutagenesis, gating currents, fluorescence studies and emerging crystal structures have started to delineate a physical representation of the conformational changes responsible for voltage sensing that lead to the opening of the conduction pore in voltage-gated ion channels. [Preview Abstract] |
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