Gaussian-Distributed Codon Frequencies of Genomes.

DNA encodes protein primary structure using 64 different codons to specify 20 different amino acids and a stop signal. Frequencies of codon occurrence when ordered in descending sequence provide a global characterization of a genome's preference (bias) for using the different codons of the redundant genetic code. Whereas frequency/rank relations have been described by empirical expressions, here we propose a statistical model in which two different forms of codon usage co-exist in a genome.

Domain and interdomain energetics underlying gating in Shaker-type Kv channels.

To understand gating events with a time-base many orders-of-magnitude slower than that of atomic motion in voltage-gated ion channels such as the Shaker-type KV channels, a multiscale physical model is constructed from the experimentally well-characterized voltage-sensor (VS) domains coupled to a hydrophobic gate. The four VS domains are described by a continuum electrostatic model under voltage-clamp conditions, the control of ion flow by the gate domain is described by a vapor-lock mechanism, and the simple coupling principle is informed by known experimental results and trial-and-error. The configurational energy computed for each element is used to produce a total Hamiltonian that is a function of applied voltage, VS positions, and gate radius.

Voltage sensing in ion channels: mesoscale simulations of biological devices.

Electrical signaling via voltage-gated ion channels depends upon the function of a voltage sensor (VS), identified with the S1-S4 domain in voltage-gated K(+) channels. Here we investigate some energetic aspects of the sliding-helix model of the VS using simulations based on VS charges, linear dielectrics, and whole-body motion. Model electrostatics in voltage-clamped boundary conditions are solved using a boundary element method.

The sliding-helix voltage sensor: mesoscale views of a robust structure-function relationship.

The voltage sensor (VS) domain of voltage-gated ion channels underlies the electrical excitability of living cells. We simulate a mesoscale model of the VS domain to determine the functional consequences of some of its physical elements. Our mesoscale model is based on VS charges, linear dielectrics, and whole-body motion, applied to an S4 "sliding helix.

Protein structure and ionic selectivity in calcium channels: selectivity filter size, not shape, matters.

Calcium channels have highly charged selectivity filters (4 COO(-) groups) that attract cations in to balance this charge and minimize free energy, forcing the cations (Na(+) and Ca(2+)) to compete for space in the filter. A reduced model was developed to better understand the mechanism of ion selectivity in calcium channels. The charge/space competition (CSC) mechanism implies that Ca(2+) is more efficient in balancing the charge of the filter because it provides twice the charge as Na(+) while occupying the same space.

Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion.

A physical model of selective "ion binding" in the L-type calcium channel is constructed, and consequences of the model are compared with experimental data. This reduced model treats only ions and the carboxylate oxygens of the EEEE locus explicitly and restricts interactions to hard-core repulsion and ion-ion and ion-dielectric electrostatic forces. The structural atoms provide a flexible environment for passing cations, thus resulting in a self-organized induced-fit model of the selectivity filter.

Molecular identity and functional properties of a novel T-type Ca2+ channel cloned from the sensory epithelia of the mouse inner ear.

The molecular identity of non-Cav1.3 channels in auditory and vestibular hair cells has remained obscure, yet the evidence in support of their roles to promote diverse Ca2+-dependent functions is indisputable. Recently, a transient Cav3.

Bubbles, gating, and anesthetics in ion channels.

We suggest that bubbles are the bistable hydrophobic gates responsible for the on-off transitions of single channel currents. In this view, many types of channels gate by the same physical mechanism-dewetting by capillary evaporation-but different types of channels use different sensors to modulate hydrophobic properties of the channel wall and thereby trigger and control bubbles and gating. Spontaneous emptying of channels has been seen in many simulations.

Volume exclusion in calcium selective channels.

Another research group has proposed an interesting model for calcium channel selectivity. However, on the basis of their reported results we find it impossible to assess the merits of their model because their results and claims concerning selectivity are based on an extrapolation over four orders of magnitude to low Ca(2+) concentration. Their results and claims have been presented in several articles and reviews in several journals and, thus, need attention.

Steric selectivity in Na channels arising from protein polarization and mobile side chains.

Monte Carlo simulations of equilibrium selectivity of Na channels with a DEKA locus are performed over a range of radius R and protein dielectric coefficient epsilon(p). Selectivity arises from the balance of electrostatic forces and steric repulsion by excluded volume of ions and side chains of the channel protein in the highly concentrated and charged (approximately 30 M) selectivity filter resembling an ionic liquid. Ions and structural side chains are described as mobile charged hard spheres that assume positions of minimal free energy.

Combined effect of pore radius and protein dielectric coefficient on the selectivity of a calcium channel.

Calcium-selective ion channels often contain a selectivity filter made of similar amino acids, rich in carboxlylates, although the Ca2+ affinities of these channels range from micromolar to millimolar. To understand the physical mechanism for this range of affinities, we use grand canonical Monte Carlo simulations to study the competition of Na+ and Ca2+ in the selectivity filter of a reduced model of a Ca channel. We show that Ca2+ affinity is increased dramatically when both the volume and dielectric coefficient of the protein are reduced.

Ca2+ selectivity of a chemically modified OmpF with reduced pore volume.

We studied an E. coli OmpF mutant (LECE) containing both an EEEE-like locus, typical of Ca(2+) channels, and an accessible and reactive cysteine. After chemical modification with the cysteine-specific, negatively charged (-1e) reagents MTSES or glutathione, this LECE mutant was tested for Ca(2+) versus alkali metal selectivity.

The effect of protein dielectric coefficient on the ionic selectivity of a calcium channel.

Calcium-selective ion channels are known to have carboxylate-rich selectivity filters, a common motif that is primarily responsible for their high Ca(2+) affinity. Different Ca(2+) affinities ranging from micromolar (the L-type Ca channel) to millimolar (the ryanodine receptor channel) are closely related to the different physiological functions of these channels. To understand the physical mechanism for this range of affinities given similar amino acids in their selectivity filters, we use grand canonical Monte Carlo simulations to assess the binding of monovalent and divalent ions in the selectivity filter of a model Ca channel.

Relating microscopic charge movement to macroscopic currents: the Ramo-Shockley theorem applied to ion channels.

Since the discovery of gating current, electrophysiologists have studied the movement of charged groups within channel proteins by changing potential and measuring the resulting capacitive current. The relation of atomic-scale movements of charged groups to the gating current measured in an external circuit, however, is not obvious. We report here that a general solution to this problem exists in the form of the Ramo-Shockley theorem.

Permeation properties of an engineered bacterial OmpF porin containing the EEEE-locus of Ca2+ channels.

The selectivity filter of the bacterial porin OmpF carries a small net charge close to -1 e and is therefore only slightly cation-selective. Calcium channels, on the other hand, contain four negatively charged glutamates, the EEEE-locus, and are among the most selective cation channels known. We aimed to turn the essentially nonselective OmpF into a Ca2+-selective channel.

Computing induced charges in inhomogeneous dielectric media: application in a Monte Carlo simulation of complex ionic systems.

The efficient calculation of induced charges in an inhomogeneous dielectric is important in simulations and coarse-grained models in molecular biology, chemical physics, and electrochemistry. We present the induced charge computation (ICC) method for the calculation of the polarization charges based on the variational formulation of Allen et al. [Phys.

Density functional theory of charged, hard-sphere fluids.

An approximate electrostatic (ES) excess free energy functional for charged, hard sphere fluids is presented. This functional is designed for systems with large density variations, but may also be applied to systems without such variations. Based on the Rosenfeld method of perturbation about a bulk (homogeneous) reference fluid [Y.

Ca2+ transport properties and determinants of anomalous mole fraction effects of single voltage-gated Ca2+ channels in hair cells from bullfrog saccule.

We studied the permeation properties of two distinct single voltage-gated Ca2+ channels in bullfrog saccular hair cells to assess the roles of the channels as physiological Ca2+ transporters and multi-ion pores. By varying the permeant ions (Ba2+, Ca2+) and concentrations (2-70 mM), we estimated the affinity constant (K(D)) of the two channels as follows (mM): L-type channel, K(D,Ba) = 7.4 +/- 1.

Binding and selectivity in L-type calcium channels: a mean spherical approximation.

L-type calcium channels are Ca(2+) binding proteins of great biological importance. They generate an essential intracellular signal of living cells by allowing Ca(2+) ions to move across the lipid membrane into the cell, thereby selecting an ion that is in low extracellular abundance. Their mechanism of selection involves four carboxylate groups, containing eight oxygen ions, that belong to the side chains of the "EEEE" locus of the channel protein, a setting similar to that found in many Ca(2+)-chelating molecules.

Ion permeation and glutamate residues linked by Poisson-Nernst-Planck theory in L-type calcium channels.

L-type Ca channels contain a cluster of four charged glutamate residues (EEEE locus), which seem essential for high Ca specificity. To understand how this highly charged structure might produce the currents and selectivity observed in this channel, a theory is needed that relates charge to current. We use an extended Poisson-Nernst-Planck (PNP2) theory to compute (mean) Coulombic interactions and thus to examine the role of the mean field electrostatic interactions in producing current and selectivity.

Anomalous mole fraction effect, electrostatics, and binding in ionic channels.

Ionic channels bathed in mixed solutions of two permeant electrolytes often conduct less current than channels bathed in pure solutions of either. For many years, this anomalous mole fraction effect (AMFE) has been thought to occur only in single-file pores containing two or more ions at a time. Most thinking about channels incorporates this view.

Attempts to define functional domains of gap junction proteins with synthetic peptides.

To map the binding sites involved in channel formation, synthetic peptides representing sequences of connexin 32 were tested for their ability to inhibit cell-cell channel formation. Both large peptides representing most of the two presumed extracellular loops of connexin32 and shorter peptides representing subsets of these larger peptides were found to inhibit cell-cell channel formation. The properties of the peptide inhibition suggested that the binding site is complex, involving several segments of both extracellular loops.

A multi-ion permeation mechanism in neuronal background chloride channels.

Unitary current/voltage relationships of background Cl channels of rat hippocampal neurons were determined for varied gradients and absolute concentrations of NaCl. The channels revealed permeabilities for both Cl and Na ions. A hyperlinear increase of unitary conductance, observed for a symmetrical increase of salt concentration from 300 and 600 mM, indicated a multi-ion permeation mechanism.

Anion-cation interactions in the pore of neuronal background chloride channels.

Background Cl channels in neurons and skeletal muscle are significantly permeable for alkali cations when tested with asymmetrical concentrations of the same salt. Both anion and cation permeation were proposed to require binding of an alkali cation with the pore (Franciolini, F., and W.