Concepts on charge transfer through naturally vibrating DNA molecule

Delocalization of charges thorough DNA occurs due to the natural and continuous movements of molecule which stimulates the charge transfer through the molecule. A model is presented showing that the mechanism of electrical conduction occurs mainly by thermally-activated drift motion of holes under control of the localized carriers; where electrons are localized in the conduction band. These localized (stationary-trapped) electrons control the movements of the positive charges and do not play an effective role in the electrical conduction itself. It is found that the localized charge-carriers in the bands have characteristic relaxation times at 5×10(^-2)s, 1.94×10(^-4)s, 5×10(^-7)s, and 2×10(^-11)s respectively which are corresponding to four intrinsic thermal activation energies 0.56eV, 0.33eV, 0.24eV, and 0.05eV respectively. The ac-conductivity of some published data are well fitted with the presented model and the total charge density in DNA molecule is calculated to be n=1.88×10(^19)cm(^-3) at 300K which is corresponding to a linear electron density n=8.66×10(^3)cm(^-1) at 300K. The model shed light on the role of transfer and/or localization of charges through DNA which has multiple applications in medical, nano-technical, bio-sensing and different domains. So, repair DNA by adjusting the charge transport through the molecule is future challenges to new medical applications.     

Microtubules as mechanical force sensors

Microtubules are polymers of tubulin subunits (dimers) arranged on a hexagonal lattice. Each tubulin dimer comprises two monomers, the alpha-tubulin and beta-tubulin, and can be found in two states. In the first state a mobile negative charge is located into the alpha-tubulin monomer and in the second into the beta-tubulin monomer. Each tubulin dimer is modeled as an electrical dipole coupled to its neighbors by electrostatic forces. The location of the mobile charge in each dimer depends on the location of the charges in the dimer's neighborhood. Mechanical forces that act on the microtubule affect the distances between the dimers and alter the electrostatic potential. Changes in this potential affect the mobile negative charge location in each dimer and the charge distribution in the microtubule. The net effect is that mechanical forces affect the charge distribution in microtubules. We propose to exploit this effect and use microtubules as mechanical force sensors. We model each dimer as a two-state quantum system and, following the quantum computation paradigm, we use discrete quantum random walk on the hexagonal microtubule lattice to determine the charge distribution. Different forces applied on the microtubule are modeled as different coin biases leading to different probability distributions of the quantum walker location, which are directly connected to different charge distributions. Simulation results show that there is a strong indication that microtubules can be used as mechanical force sensors and that they can also detect the force directions and magnitudes.     

Molecular Dynamics Simulations with Interaction Potentials Including Polarization Development of a Noniterative Method and Application to Water

A general method is suggested for the implementation of polarization in molecular dynamics simulations of small molecules. Induced dipole moments are evaluated on selected polarizability centers and represented by separation of charges. The positive polarization charges reside on the selected atoms. The negative polarization charges are treated as additional particles. The positions of these polarization charges are determined from the electrical fields due to the permanent charges of the system. Thus the induction is treated explicitly, while the higher order contributions, the polarization due to induced dipoles, are taken into account in an average way by modification of potential parameters. The forces can be evaluated for the new charge distribution in the conventional way. As an illustration of this approach initial results are reported for the development of a polarizable water model. The higher order polarization is treated in an average way by slight increase of the permanent charges as compared to the values that would give the gas phase dipole moment. The increase in CPU time is comparable to the addition of one atom per polarizable center.     

Are extracellular osmolality and sodium concentration determined by Donnan effects of intracellular protein charges and of pumped sodium?

Although we are used to attribute almost identical extracellular fluid (ECF) sodium concentrations in birds, amphibians, reptiles, and mammals to the composition of the primordial oceans in which, presumably, all life originated, this interpretation is not supported by geological data suggesting that the ocean salinity was never much lower than the present-day values, still four times higher than our plasma sodium.Here presented interpretation is that the similar ECF salt concentrations are dictated by the opposed Donnan effects on the cell membrane. The only way for the cell to reach the osmotic equilibrium is to alter cell volume, until concentration of nondiffusible intracellular ions (mainly charges on intracellular proteins) is equal to the ECF restricted ions (mainly Na⁺ ions, restricted by pumping out of cells).The achievement of electroneutrality requires that the sum of all anions equals concentration of positive ions in the cell (mainly K⁺). Negative charges on cytoplasmic proteins are the most stable component among ionized particles and other ions have to adapt to their concentration. Positive and negative soluble intracellular ions are all osmotically active and to achieve balance of osmotic forces on the cell membrane, the sum of their intracellular concentrations must equal the concentration of osmotically active extracellular particles. Since almost half the osmotically active ECF particles are sodium ions, the ECF sodium concentration seems related to concentration of charges on cytoplasmic proteins and concentration of intracellular phosphates.Our ancestors could not leave the salty ocean and move to brackish, or even fresh waters, without adequate regulation of their ECF sodium concentration and osmolality. Concentration of charges on cytoplasmic proteins or of intracellular phosphate buffers could not be altered, since this would compromise cell functioning. The remaining solution was to maintain the lowest ECF Na⁺ concentration effective in counteracting the average Donnan effect of charges on cytoplasmic proteins. When the optimal ECF sodium concentration had once become the reference point for osmoreceptors (controlling thirst and ADH secretion) and other regulatory mechanisms (secretion of renin/angiotensin/aldosterone, natriuretic factors), it made an important survival advantage that allowed spreading of animal life in fresh water and conquering of earth. The actual common value had to be a compromise that reduces the average osmotic burden on body cells to zero. Individual cells can reduce eventual residual osmotic forces on their membrane through altering cell volume by chloride shift, and by modulating the Na⁺K⁺-ATPase function.     

Endogenous L-glutamate transport in oocytes of Xenopus laevis.

The existence of an endogenous Na(+)-glutamate cotransporter in the oocytes of Xenopus laevis is demonstrated. The transporter does not accept D-glutamate as substrate. The dependence on substrate displays two saturating components with low (K1/2 = 9 mM) and high (K1/2 = 0.35 microM) affinities for L-glutamate. The dependence on external Na+ exhibits a saturating component with a K1/2 value of about 5 mM and a component that has not saturated up to 110 mM Na+. In voltage-clamped oocytes, it is possible to demonstrate that Na(+)-dependent L-glutamate transport is directly coupled to countertransport of Rb+. The analysis of the voltage dependence of the Na+,K(+)-dependent L-glutamate uptake suggests that positive charges are moved inwardly during the transport cycle.     

Spatial Configuration and Composition of Charge Modulates Transport into a Mucin Hydrogel Barrier

The mucus barrier is selectively permeable to a wide variety of molecules, proteins, and cells, and establishes gradients of these particulates to influence the uptake of nutrients, the defense against pathogens, and the delivery of drugs. Despite its importance for health and disease, the criteria that govern transport through the mucus barrier are largely unknown. Studies with uniformly functionalized nanoparticles have provided critical information about the relevance of particle size and net charge for mucus transport. However, these particles lack the detailed spatial arrangements of charge found in natural mucus-interacting substrates, such as certain viruses, which may have important consequences for transport through the mucus barrier. Using a novel, to our knowledge, microfluidic design that enables us to measure real-time transport gradients inside a hydrogel of mucins, the gel-forming glycoprotein component of mucus, we show that two peptides with the same net charge, but different charge arrangements, exhibit fundamentally different transport behaviors. Specifically, we show that certain configurations of positive and negative charges result in enhanced uptake into a mucin barrier, a remarkable effect that is not observed with either charge alone. Moreover, we show that the ionic strength within the mucin barrier strongly influences transport specificity, and that this effect depends on the detailed spatial arrangement of charge. These findings suggest that spatial charge distribution is a critical parameter to modulate transport through mucin-based barriers, and have concrete implications for the prediction of mucosal passage, and the design of drug delivery vehicles with tunable transport properties.     

Electrical conductivity of a partially ionized plasma with allowance for the effect of plasma screening on the electron scattering by neutral atoms

Using linear response theory, the effect of electron-atom scattering on the electrical conductivity of a partially ionized hydrogen plasma is studied in the relevant statistical operator approximation. A relationship is analyzed between the polarization potential, which is routinely used in the problem, and the adiabatic potential, which results from the separation of electrons into bound and unbound ones. An approximation accounting for the effect of unbound electrons on the interaction between neutral and charged plasma particles is constructed. It is found that, in a high-density plasma, the parameters of the interaction of an atom with charged particles can change significantly, so these changes should be taken into account in calculating kinetic plasma properties.     

Stochastic models of neuronal dynamics

Cortical activity is the product of interactions among neuronal populations. Macroscopic electrophysiological phenomena are generated by these interactions. In principle, the mechanisms of these interactions afford constraints on biologically plausible models of electrophysiological responses. In other words, the macroscopic features of cortical activity can be modelled in terms of the microscopic behaviour of neurons. An evoked response potential (ERP) is the mean electrical potential measured from an electrode on the scalp, in response to some event. The purpose of this paper is to outline a population density approach to modelling ERPs.We propose a biologically plausible model of neuronal activity that enables the estimation of physiologically meaningful parameters from electrophysiological data. The model encompasses four basic characteristics of neuronal activity and organization: (i) neurons are dynamic units, (ii) driven by stochastic forces, (iii) organized into populations with similar biophysical properties and response characteristics and (iv) multiple populations interact to form functional networks. This leads to a formulation of population dynamics in terms of the Fokker-Planck equation. The solution of this equation is the temporal evolution of a probability density over state-space, representing the distribution of an ensemble of trajectories. Each trajectory corresponds to the changing state of a neuron. Measurements can be modelled by taking expectations over this density, e.g. mean membrane potential, firing rate or energy consumption per neuron. The key motivation behind our approach is that ERPs represent an average response over many neurons. This means it is sufficient to model the probability density over neurons, because this implicitly models their average state. Although the dynamics of each neuron can be highly stochastic, the dynamics of the density is not. This means we can use Bayesian inference and estimation tools that have already been established for deterministic systems. The potential importance of modelling density dynamics (as opposed to more conventional neural mass models) is that they include interactions among the moments of neuronal states (e.g. the mean depolarization may depend on the variance of synaptic currents through nonlinear mechanisms).Here, we formulate a population model, based on biologically informed model-neurons with spike-rate adaptation and synaptic dynamics. Neuronal sub-populations are coupled to form an observation model, with the aim of estimating and making inferences about coupling among sub-populations using real data. We approximate the time-dependent solution of the system using a bi-orthogonal set and first-order perturbation expansion. For didactic purposes, the model is developed first in the context of deterministic input, and then extended to include stochastic effects. The approach is demonstrated using synthetic data, where model parameters are identified using a Bayesian estimation scheme we have described previously.     

Long-range interactions, voltage sensitivity, and ion conduction in S4 segments of excitable channels.

Forces acting on the S4 segments of the channel, the voltage-sensing structures, are analyzed. The conformational change in the Na channel is modeled as a helix-coil transition in the four S4 segments, coupled to the membrane voltage by electrical forces. In the model, repulsions between like charges make the S4 segment unstable, but field-dependent forces hold it in an alpha-helix configuration at resting potential. At threshold depolarization, the S4 helices cooperatively expand into random coils, breaking the hydrogen bonds connecting adjacent loops of the alpha helices. Exposed electron pairs left on the carbonyl oxygens constitute sites at which cations can bind selectively. The first hydrogen bond to break is at the channel exterior, then the second breaks, and so on in a zipper-like motion along the entire segment. The Na+ ions hop from one site to the next until all H bonds are broken and all sites are filled with ions. This completes the pathway over which the permeant ions move through the channel, driven by the electrochemical potential difference across the membrane. This microscopic mechanism is consistent with the thermodynamic explanation of ion-channel gating previously formulated as the ferroelectric-superionic transition hypothesis.     

Detection of DNA recognition events using multi-well field effect devices

We proposed the multi-well field effect device for detection of charged biomolecules and demonstrated the detection principle for DNA recognition events using quasi-static capacitance-voltage (QSCV) measurement. The multi-well field effect device is based on the electrostatic interaction between molecular charges induced by DNA recognition and surface electrons in silicon through the Si(3)N(4)/SiO(2) thin double-layer. Since DNA molecules and DNA binders such as Hoechst 33258 have intrinsic charges in aqueous solutions, respectively, the charge density changes due to DNA recognition events at the Si(3)N(4) surface were directly translated into electrical signal such as a flat band voltage change in the QSCV measurement. The average flat band shifts were 20.7 mV for hybridization and -13.5 mV for binding of Hoechst 33258. From the results of flat band voltage shifts due to hybridization and binding of Hoechst 33258, the immobilization density of oligonucleotide probes at the Si(3)N(4) surface was estimated to be 10(8) cm(-2). The platform based on the multi-well field effect device is suitable for a simple and arrayed detection system for DNA recognition events.     

THE INFLUENCE OF ELECTROLYTES ON THE ELECTRIFICATION AND THE RATE OF DIFFUSION OF WATER THROUGH COLLODION MEMBRANES

1. When pure water is separated by a collodion membrane from a watery solution of an electrolyte the rate of diffusion of water is influenced not only by the forces of gas pressure but also by electrical forces. 2. Water is in this case attracted by the solute as if the molecules of water were charged electrically, the sign of the charge of the water particles as well as the strength of the attractive force finding expression in the following two rules, (a) Solutions of neutral salts possessing a univalent or bivalent cation influence the rate of diffusion of water through a collodion membrane, as if the water particles were charged positively and were attracted by the anion and repelled by the cation of the electrolyte; the attractive and repulsive action increasing with the number of charges of the ion and diminishing inversely with a quantity which we will designate arbitrarily as the "radius" of the ion. The same rule applies to solutions of alkalies. (b) Solutions of neutral or acid salts possessing a trivalent or tetravalent cation influence the rate of diffusion of water through a collodion membrane as if the particles of water were charged negatively and were attracted by the cation and repelled by the anion of the electrolyte. Solutions of acids obey the same rule, the high electrostatic effect of the hydrogen ion being probably due to its small "ionic radius." 3. The correctness of the assumption made in these rules concerning the sign of the charge of the water particles is proved by experiments on electrical osmose. 4. A method is given by which the strength of the attractive electric force of electrolytes on the molecules of water can be roughly estimated and the results of these measurements are in agreement with the two rules. 5. The electric attraction of water caused by the electrolyte increases with an increase in the concentration of the electrolyte, but at low concentrations more rapidly than at high concentrations. A tentative explanation for this phenomenon is offered. 6. The rate of diffusion of an electrolyte from a solution to pure solvent through a collodion membrane seems to obey largely the kinetic theory inasmuch as the number of molecules of solute diffusing through the unit of area of the membrane in unit time is (as long as the concentration is not too low) approximately proportional to the concentration of the electrolyte and is the same for the same concentrations of LiCl, NaCl, MgCl₂, and CaCl₂.     

Bio-microrheology: a frontier in microrheology

Cells continuously adapt to changing conditions through coordinated molecular and mechanical responses. This adaptation requires the transport of molecules and signaling through intracellular regions with differing material properties, such as variations in viscosity or elasticity. To determine the impact of regional variations on cell structure and physiology, an approach, termed bio-microrheology, or the study of deformation and flow of biological materials at small length scales has emerged. By tracking the thermal and driven motion of probe particles, organelles, or molecules, the local physical environment in distinct subcellular regions can be explored. On the surface or inside cells, tracking the motion of particles can reveal the rheological properties that influence cell features, such as shape and metastatic potential. Cellular microrheology promises to improve our concepts of regional and integrated properties, structures, and transport in live cells. Since bio-microrheology is an evolving methodology, many specific details, such as how to interpret complex combinations of thermally mediated and directed probe transport, remain to be fully explained. This work reviews the current state of the field and discusses the utility and challenges of this emerging approach.     

Evidence for a central role for electro-osmosis in fluid transport by corneal endothelium

The mechanism of transepithelial fluid transport remains unclear. The prevailing explanation is that transport of electrolytes across cell membranes results in local concentration gradients and transcellular osmosis. However, when transporting fluid, the corneal endothelium spontaneously generates a locally circulating current of approximately 25 microA cm(-2), and we report here that electrical currents (0 to +/-15 microA cm(-2)) imposed across this layer induce fluid movements linear with the currents. As the imposed currents must be approximately 98% paracellular, the direction of induced fluid movements and the rapidity with which they follow current imposition (rise time < or =3 sec) is consistent with electro-osmosis driven by sodium movement across the paracellular pathway. The value of the coupling coefficient between current and fluid movements found here (2.37 +/- 0.11 microm cm(2) hr(-1) microA (-1), suggests that: 1) the local endothelial current accounts for spontaneous transendothelial fluid transport; 2) the fluid transported becomes isotonically equilibrated. Ca(++)-free solutions or endothelial damage eliminate the coupling, pointing to the cells and particularly their intercellular junctions as a main site of electro-osmosis. The polycation polylysine, which is expected to affect surface charges, reverses the direction of current-induced fluid movements. Fluid transport is proportional to the electrical resistance of the ambient medium. Taken together, the results suggest that electro-osmosis through the intercellular junctions is the primary process in a sequence of events that results in fluid transport across this preparation.     

A kinetic perspective on extracellular electron transfer by anode-respiring bacteria

In microbial fuel cells and electrolysis cells (MXCs), anode-respiring bacteria (ARB) oxidize organic substrates to produce electrical current. In order to develop an electrical current, ARB must transfer electrons to a solid anode through extracellular electron transfer (EET). ARB use various EET mechanisms to transfer electrons to the anode, including direct contact through outer-membrane proteins, diffusion of soluble electron shuttles, and electron transport through solid components of the extracellular biofilm matrix. In this review, we perform a novel kinetic analysis of each EET mechanism by analyzing the results available in the literature. Our goal is to evaluate how well each EET mechanism can produce a high current density (>10 A m⁻²) without a large anode potential loss (less than a few hundred millivolts), which are feasibility goals of MXCs. Direct contact of ARB to the anode cannot achieve high current densities due to the limited number of cells that can come in direct contact with the anode. Slow diffusive flux of electron shuttles at commonly observed concentrations limits current generation and results in high potential losses, as has been observed experimentally. Only electron transport through a solid conductive matrix can explain observations of high current densities and low anode potential losses. Thus, a study of the biological components that create a solid conductive matrix is of critical importance for understanding the function of ARB.     

Model of multifractal gating of single ionic channels in biological membranes

A physico-mathematical model of the gating machinery of single ionic channels in biological membranes has been developed. In the paradigm of this model, gating particles are subjected to: (i) deterministic friction force responsible for interactions of gating particles with the surrounding solution; (ii) deterministic potential force depending on the structure and conformational state of the channel pore (the latter is controlled by the transmembrane voltage V and regulates the motion of particles overcoming potential barriers on going from the closed (open) to the open (closed) state of the channel); (iii) deterministic force responsible for interactions of water molecules with hydrophobic sites in the channel pore, and, finally, (iv) stochastic thermal fluctuation force. The model affords adequate approximation of experimental data.     

The relationship between the electrochemical proton gradient and active transport in Escherichia coli membrane vesicles.

In the previous paper [ramos, S., and Kaback, H.R. (1977), Biochemistry 16 (preceding paper in this issue)], it was demonstrated that Escherichia coli membrane vesicles generate a large electrochemical proton gradient (delta-muH+) under appropriate conditions, and some of the properties of delta-muH+ and its component forces [i.e., the membrane potential (delta psi) and the chemical gradient of protons (deltapH)] were described. In this paper, the relationship between delta-muH+, delta psi, and deltapH and the active transport of specific solutes is examined. Addition of lactose or glucose 6-phosphate to membrane vesicles containing the appropriate transport systems results in partial collapse of deltapH, providing direct evidence for the suggestion that respiratory energy can drive active transport via the pH gradient across the membrane. Titration studies with valinomycin and nigericin lead to the conclusion that, at pH 5.5, there are two general classes of transport systems: those that are driven primarily by delta-muH+ (lactose, proline, serine, glycine, tyrosine, glutamate, leucine, lysine, cysteine, and succinate) and those that are driven primarily by deltapH (glucose 6-phosphate, D-lactate, glucuronate, and gluconate). Importantly, however, it is also demonstrated that at pH 7.5, all of these transport systems are driven by delta psi which comprises the only component of delta-muH+ at this external pH. In addition, the effect of external pH on the steady-state levels of accumulation of different solutes is examined, and it is shown that none of the pH profiles correspond to those observed for delta-muH+, delta psi, or deltapH. Moreover, at external pH values above 6.0-6.5, delta-muH+ is insufficient to account for the concentration gradients established for each substrate unless the stoichiometry between protons and accumulated solutes is greater than unity. The results confirm many facets of the chemiosmotic hypothesis, but they also extend the concept in certain important respects and allow explanations for some earlier observations which seemed to preclude the involvement of chemiosmotic phenomena in active transport.     

Direct Cytoskeleton Forces Cause Membrane Softening in Red Blood Cells

Erythrocytes are flexible cells specialized in the systemic transport of oxygen in vertebrates. This physiological function is connected to their outstanding ability to deform in passing through narrow capillaries. In recent years, there has been an influx of experimental evidence of enhanced cell-shape fluctuations related to metabolically driven activity of the erythroid membrane skeleton. However, no direct observation of the active cytoskeleton forces has yet been reported to our knowledge. Here, we show experimental evidence of the presence of temporally correlated forces superposed over the thermal fluctuations of the erythrocyte membrane. These forces are ATP-dependent and drive enhanced flickering motions in human erythrocytes. Theoretical analyses provide support for a direct force exerted on the membrane by the cytoskeleton nodes as pulses of well-defined average duration. In addition, such metabolically regulated active forces cause global membrane softening, a mechanical attribute related to the functional erythroid deformability.     

Breathing and bending fluctuations in DNA modeled by an open-base-pair kink coupled to axial compression

We develop a model designed to show that flexibility in the DNA molecule can arise from relatively improbable transient opening of base pairs. The axial direction changes at the site of an open base pair. The region between open base pairs is a double helix of hydrogen-bonded base pairs with a slightly decreased rise per residue and a slightly increased helical winding angle. An analysis of the model yields several testable predictions. For example, we predict probability 0.026 for a base pair to be open at 25°C, a value close to that measured by hydrogen-exchange experiments. Other predictions involve matters like the variation of persistence length with ionic strength and temperature, the variation of helical winding angle with temperature, and the kinetics of heat denaturation. An additional result of the analysis is an explanation of the high degree of local stiffness of the DNA molecule. Strong resistance to bending fluctuations is provided from two sources: increased polyelectrolyte repulsion among phosphate groups in the axially compressed stacks between open base pairs and the tendency of stacking forces to oppose opening of a base pair. Stacking forces, however, also support compression of the stacks between open base pairs, so that the net effect of stacking forces on elastic bending of DNA is small relative to the polyelectrolyte effect. If the ionic charges on the phosphate groups were absent, DNA would spontaneously fold, driven by the entropy gained when about 1% of its base pairs open.     

Protein and DNA reactions stimulated by electromagnetic fields

The stimulation of protein and DNA by electromagnetic fields (EMF) has been problematic because the fields do not appear to have sufficient energy to directly affect such large molecules. Studies with electric and magnetic fields in the extremely low-frequency range have shown that weak fields can cause charge movement. It has also been known for some time that redistribution of charges in large molecules can trigger conformational changes that are driven by large hydration energies. This review considers examples of direct effects of electric and magnetic fields on charge transfer, and structural changes driven by such changes. Conformational changes that arise from alterations in charge distribution play a key role in membrane transport proteins, including ion channels, and probably account for DNA stimulation to initiate protein synthesis. It appears likely that weak EMF can control and amplify biological processes through their effects on charge distribution.