Microtubule ionic conduction and its implications for higher cognitive functions.

The neuronal cytoskeleton has been hypothesized to play a role in higher cognitive functions including learning, memory and consciousness. Experimental evidence suggests that both microtubules and actin filaments act as biological electrical wires that can transmit and amplify electric signals via the flow of condensed ion clouds. The potential transmission of electrical signals via the cytoskeleton is of extreme importance to the electrical activity of neurons in general.

Estimation of the number of biophotons involved in the visual perception of a single-object image: biophoton intensity can be considerably higher inside cells than outside.

Recently, we have proposed a redox molecular hypothesis about the natural biophysical substrate of visual perception and imagery [1,6]. Namely, the retina transforms external photon signals into electrical signals that are carried to the V1 (striatecortex). Then, V1 retinotopic electrical signals (spike-related electrical signals along classical axonal-dendritic pathways) can be converted into regulated ultraweak bioluminescent photons (biophotons) through redox processes within retinotopic visual neurons that make it possible to create intrinsic biophysical pictures during visual perception and imagery.

Computational design and biological testing of highly cytotoxic colchicine ring A modifications.

Microtubules are the primary target for many anti-cancer drugs, the majority of which bind specifically to beta-tubulin. The existence of several beta-tubulin isotypes, coupled with their varied expression in normal and cancerous cells provides a platform upon which to construct selective chemotherapeutic agents. We have examined five prevalent human beta-tubulin isotypes and identified the colchicine-binding site as the most promising for drug design based on specificity.

Torsional elastic deformations of microtubules within continuous sheet model.

This paper develops a rigorous analysis of the microtubule elastic deformations in terms of the torsional degrees of freedom using the helix-based cylindrical structure of this biopolymer. Methods of differential geometry and the theory of elasticity are employed in our analysis. We find equilibrium conditions and constitutive equations in the linear regime.

Explicitly solvated ligand contribution to continuum solvation models for binding free energies: selectivity of theophylline binding to an RNA aptamer.

To provide more accurate computational estimates of binding free energies in solution from molecular dynamics (MD) simulations, a separate solvation contribution for the binding ligand is determined from a linear response treatment. We use explicit water coordinates for this term and combine with MM-PBSA (molecular mechanics, Poisson-Boltzmann, and surface area contributions) in a new approach (MM-PB/LRA-SA). To assess this method, application to the binding between theophylline and its derivatives to an RNA aptamer was performed and compared with experimental binding affinities.

Cancer proliferation and therapy: the Warburg effect and quantum metabolism.

Background: Most cancer cells, in contrast to normal differentiated cells, rely on aerobic glycolysis instead of oxidative phosphorylation to generate metabolic energy, a phenomenon called the Warburg effect.

Model: Quantum metabolism is an analytic theory of metabolic regulation which exploits the methodology of quantum mechanics to derive allometric rules relating cellular metabolic rate and cell size. This theory explains differences in the metabolic rates of cells utilizing OxPhos and cells utilizing glycolysis.

Electrostatic contributions to colchicine binding within tubulin isotypes.

Tubulin, the structural subunit of microtubules, is the target of some highly successful anti-tumor drugs. Most of these drugs bind to the beta-tubulin resulting in the inhibition of microtubule dynamics and eventually cell death. The varied cellular distribution of several human isotypes of beta -tubulin provides a platform upon which to construct novel chemotherapeutic agents that are able to differentiate between these types of cells.

Continuous model for microtubule dynamics with catastrophe, rescue, and nucleation processes.

Microtubules are a major component of the cytoskeleton distinguished by highly dynamic behavior both in vitro and in vivo referred to as dynamic instability. We propose a general mathematical model that accounts for the growth, catastrophe, rescue, and nucleation processes in the polymerization of microtubules from tubulin dimers. Our model is an extension of various mathematical models developed earlier formulated in order to capture and unify the various aspects of tubulin polymerization.

Quantum metabolism explains the allometric scaling of metabolic rates.

A general model explaining the origin of allometric laws of physiology is proposed based on coupled energy-transducing oscillator networks embedded in a physical d-dimensional space (d = 1, 2, 3). This approach integrates Mitchell's theory of chemi-osmosis with the Debye model of the thermal properties of solids. We derive a scaling rule that relates the energy generated by redox reactions in cells, the dimensionality of the physical space and the mean cycle time.

Effect of calcium on electrical energy transfer by microtubules.

Microtubules (MTs) are important cytoskeletal superstructures implicated in neuronal morphology and function, which are involved in vesicle trafficking, neurite formation and differentiation and other morphological changes. The structural and functional properties of MTs depend on their high intrinsic charge density and functional regulation by the MT depolymerising properties of changes in Ca(2 + ) concentration. Recently, we reported on remarkable properties of isolated MTs, which behave as biomolecular transistors capable of amplifying electrical signals (Priel et al.

Neural cytoskeleton capabilities for learning and memory.

This paper proposes a physical model involving the key structures within the neural cytoskeleton as major players in molecular-level processing of information required for learning and memory storage. In particular, actin filaments and microtubules are macromolecules having highly charged surfaces that enable them to conduct electric signals. The biophysical properties of these filaments relevant to the conduction of ionic current include a condensation of counterions on the filament surface and a nonlinear complex physical structure conducive to the generation of modulated waves.

A critical assessment of the information processing capabilities of neuronal microtubules using coherent excitations.

Evidence for signaling, communication, and conductivity in microtubules (MTs) has been shown through both direct and indirect means, and theoretical models predict their potential use in both classical and quantum information processing in neurons. The notion of quantum information processing within neurons has been implicated in the phenomena of consciousness, although controversies have arisen in regards to adverse physiological temperature effects on these capabilities. To investigate the possibility of quantum processes in relation to information processing in MTs, a biophysical MT model is used based on the electrostatic interior of the tubulin protein.

Viscous drag effect in the flexural rigidity and cantilever stiffness of bio- and nano-filaments measured with the shooting-bead method.

The so-called shooting-bead method is a fast and easy experimental technique for evaluating cantilever stiffness and flexural rigidity of semiflexible to semirigid rodlike biological and nano-filaments based on the measurement of just two distances. In this paper we have derived the shooting-bead formula for cantilever stiffness and flexural rigidity taking into account the effects of the viscous drag force exerted on the filament itself. To this end, we have defined a key variable, called the filament energy-loss factor (or filament drag factor), which accounts for all the energy-loss effects.

Information processing mechanisms in microtubules at physiological temperature: Model predictions for experimental tests.

Both direct and indirect experimental evidence has shown signaling, communication and conductivity in microtubules (MTs). Theoretical models have predicted that MTs can be potentially used for both classical and quantum information processing although controversies arose in regard to physiological temperature effects on these capabilities. In this paper, MTs have been studied using well-established principles of classical statistical physics as applied to information processing, information storage and signal propagation.

Identification and characterization of an intermediate taxol binding site within microtubule nanopores and a mechanism for tubulin isotype binding selectivity.

Tubulin, the primary subunit of microtubules, is remarkable for the variety of small molecules to which it binds. Many of these are very useful or promising agents in cancer chemotherapy. One of the most useful of these is paclitaxel.

A nonlinear model of ionic wave propagation along microtubules.

Microtubules (MTs) are important cytoskeletal polymers engaged in a number of specific cellular activities including the traffic of organelles using motor proteins, cellular architecture and motility, cell division and a possible participation in information processing within neuronal functioning. How MTs operate and process electrical information is still largely unknown. In this paper we investigate the conditions enabling MTs to act as electrical transmission lines for ion flows along their lengths.

Identification of tubulin drug binding sites and prediction of relative differences in binding affinities to tubulin isotypes using digital signal processing.

Microtubules are involved in numerous cellular processes including chromosome segregation during mitosis and, as a result, their constituent protein, tubulin, has become a successful target of several chemotherapeutic drugs. In general, these drugs bind indiscriminately to tubulin within both cancerous and healthy cells, resulting in unwanted side effects. However, differences between beta-tubulin isotypes expressed in a wide range of cell types may aid in the development of anti-tubulin drugs having increased specificity for only certain types of cells.

Modelling the role of intrinsic electric fields in microtubules as an additional control mechanism of bi-directional intracellular transport.

Active transport is essential for cellular function, while impaired transport has been linked to diseases such as neuronal degeneration. Much long distance transport in cells uses opposite polarity molecular motors of the kinesin and dynein families to move cargos along microtubules. It is clear that many types of cargo are moved by both sets of motors, and frequently in a reverse direction.

Emergence of power laws in the pharmacokinetics of paclitaxel due to competing saturable processes.

Purpose: This study presents the results of power law analysis applied to the pharmacokinetics of paclitaxel. Emphasis is placed on the role that the power exponent can play in the investigation and quantification of nonlinear pharmacokinetics and the elucidation of the underlying physiological processes.

Methods: Forty-one sets of concentration-time data were inferred from 20 published clinical trial studies, and 8 sets of area-under-the-curve (AUC) and maximum concentration (Cmax) values as a function of dose were collected.

Microtubule assembly of isotypically purified tubulin and its mixtures.

Numerous isotypes of the structural protein tubulin have now been characterized in various organisms and their expression offers a plausible explanation for observed differences affecting microtubule function in vivo. While this is an attractive hypothesis, there are only a handful of studies demonstrating a direct influence of tubulin isotype composition on the dynamic properties of microtubules. Here, we present the results of experimental assays on the assembly of microtubules from bovine brain tubulin using purified isotypes at various controlled relative concentrations.

Rayleigh instability of the inverted one-cell amphibian embryo.

The one-cell amphibian embryo is modeled as a rigid spherical shell containing equal volumes of two immiscible fluids with different densities and viscosities and a surface tension between them. The fluids represent denser yolk in the bottom hemisphere and clearer cytoplasm and the germinal vesicle in the top hemisphere. The unstable equilibrium configuration of the inverted system (the heavier fluid on top) depends on the value of the contact angle.

Improving the performance of the coupled reference interaction site model-hyper-netted chain (RISM-HNC)/simulation method for free energy of solvation.

The coupled reference interaction site model-hyper-netted chain (RISM-HNC)/ simulation methodology determines solvation free energies as a function of the set of all radial distribution functions of solvent atoms about atomic solute sites. These functions are determined from molecular dynamics (MD) or Monte Carlo (MC) simulations rather than from solving the RISM and HNC equations iteratively. Previous applications of the method showed that it can predict relative free energies of solvation for small solutes accurately.

Analysis of protein three-dimension structure using amino acids depths.

The issue of amino acid depth in proteins gives important insights to our understanding of protein's three-dimensional structure. There has already been much research done in mathematical and statistical sciences regarding the general definitions, properties and algorithms describing the particle depth of spatially extended systems. We constructed a method of calculating the amino acids depths and applied it to a set of 527 protein structures.

Complex movements of motor protein relay helices during the power stroke.

We use the Toda soliton formalism to propose a possible complex movement of alpha helices with a very important role in energy transduction during the power stroke of motor proteins. We find that this approach has advantages in comparison with the Davydov soliton model and its variants. We estimated the model's parameters and calculated corresponding properties of the predicted solitary waves including propagation velocities and energies.