Electrical Propagation of Condensed and Diffuse Ions Along Actin Filaments.

In this article, we elucidate the roles of divalent ion condensation and highly polarized immobile water molecules on the propagation of ionic calcium waves along actin filaments. We introduced a novel electrical triple layer model and used a non-linear Debye-Huckel theory with a non-linear, dissipative, electrical transmission line model to characterize the physicochemical properties of each monomer in the filament. This characterization is carried out in terms of an electric circuit model containing monomeric flow resistances and ionic capacitances in both the condensed and diffuse layers. We considered resting and excited states of a neuron using representative mono and divalent electrolyte mixtures. Additionally, we used 0.05V and 0.15V voltage inputs to study ionic waves along actin filaments in voltage clamp experiments. Our results reveal that the physicochemical properties characterizing the condensed and diffuse layers lead to different electrical conductive mediums depending on the ionic species and the neuron state. This region specific propagation mechanism provides a more realistic avenue of delivery by way of cytoskeleton filaments for larger charged cationic species. A new direct path for transporting divalent ions might be crucial for many electrical processes found in localized neuron elements such as at mitochondria and dendritic spines.

Electrical impulse characterization along actin filaments in pathological conditions.

We present an interactive Mathematica notebook that characterizes the electrical impulses along actin filaments in both muscle and non-muscle cells for a wide range of physiological and pathological conditions. The simplicity of the theoretical formulation, and high performance of the Mathematica software, enable the analysis of multiple conditions without computational restrictions. The program is based on a multi-scale (atomic → monomer → filament) approach capable of accounting for the atomistic details of a protein molecular structure, its biological environment, and their impact on the travel distance, velocity, and attenuation of monovalent ionic wave packets propagating along microfilaments. The interactive component allows investigators to choose the experimental conditions (intracellular Vs in vitro), nucleotide state (ATP Vs ADP), actin isoform (alpha, gamma, beta, and muscle or non-muscle cell), as well as a conformation model that covers a variety of mutants and wild-type (the control) actin filament. We used the computational tool to analyze environmental changes such as temperature effects and pH changes of the surrounding solutions, as well as structural changes to an actin monomer due to radius changes. Additionally, we investigated for the first time the electrostatic consequences of actin mutations from different disease conditions. These studies may provide an unprecedented molecular understanding of why and how age, inheritance, and disease conditions induce dysfunctions in the biophysical mechanisms underlying the propagation of electrical signals along actin filaments.

A Java Application to Characterize Biomolecules and Nanomaterials in Electrolyte Aqueous Solutions.

The electrostatic, entropic and surface interactions between a macroion (nanoparticle or biomolecule), surrounding ions and water molecules play a fundamental role in the behavior and function of colloidal systems. However, the molecular mechanisms governing these phenomena are still poorly understood. One of the major limitations in procuring this understanding is the lack of appropriate computational tools. Additionally, only experts in the field with an extensive background in programming, who are trained in statistical mechanics, and have access to supercomputers are able to study these systems. To overcome these limitations, in this article, we present a free, multiplatform, portable Java software, which provides experts and non-experts in the field an easy and efficient way to obtain an accurate molecular characterization of electrical and structural properties of aqueous electrolyte mixture solutions around both cylindrical- and spherical-like rigid macroions under multiple conditions. These properties include the normalized ions and water density profile distributions, the mean electrostatic potential, the integrated charge, the zeta potential, the electrostatic potential energy, the particle crowding entropy energy, the ion-ion electrostatic direct correlation energy, and the ionic potential of mean force. The Java software does not require outstanding skills and comes with detailed user-guide documentation. The application is based on the so-called Classical Density Functional Theory Solver (CSDFTS), which was successfully applied to a variety of rod-like biopolymers, rigid-like globular proteins, nanoparticles, and nano-rods. CSDFTS implements several electrolyte and macroion models, uses different levels of approximation and takes advantage of high performance Fortran90 routines and optimized libraries. These features enable the software to run on single processor computers at low-to-moderate computational cost depending on the computer performance, the grid resolution, and the characterization of the macroion and the electrolyte solution, among other factors. As a unique feature, the software comes with a graphical user interface (GUI) that allows users to take advantage of the visually guided setup of the required input data to properly characterize the system and configure the solver. Several examples on nanomaterials and biomolecules are provided to illustrate the use of the GUI and the solver performance.

Electrical double layer properties of spherical oxide nanoparticles.

The accurate characterization of the electrical double layer properties of nanoparticles is of fundamental importance for optimizing their physicochemical properties for specific biotechnological and biomedical applications. In this article, we use classical solvation density functional theory and a surface complexation model to investigate the effects of the pH and the nanoparticle size on the structural and electrostatic properties of an electrolyte solution surrounding a spherical silica oxide nanoparticle. The formulation has been particularly useful for identifying dominant interactions governing the ionic driving force at a variety of pH levels and nanoparticle sizes. As a result of the energetic interplay displayed between electrostatic potential, ion-ion correlation and particle crowding effects on the nanoparticle surface titration, rich, non-trivial ion density profiles and mean electrostatic potential behavior have been found.

MPBEC, a Matlab Program for Biomolecular Electrostatic Calculations.

One of the most used and efficient approaches to compute electrostatic properties of biological systems is to numerically solve the Poisson-Boltzmann (PB) equation. There are several software packages available that solve the PB equation for molecules in aqueous electrolyte solutions. Most of these software packages are useful for scientists with specialized training and expertise in computational biophysics. However, the user is usually required to manually take several important choices, depending on the complexity of the biological system, to successfully obtain the numerical solution of the PB equation. This may become an obstacle for researchers, experimentalists, even students with no special training in computational methodologies. Aiming to overcome this limitation, in this article we present MPBEC, a free, cross-platform, open-source software that provides non-experts in the field an easy and efficient way to perform biomolecular electrostatic calculations on single processor computers. MPBEC is a Matlab script based on the Adaptative Poisson Boltzmann Solver, one of the most popular approaches used to solve the PB equation. MPBEC does not require any user programming, text editing or extensive statistical skills, and comes with detailed user-guide documentation. As a unique feature, MPBEC includes a useful graphical user interface (GUI) application which helps and guides users to configure and setup the optimal parameters and approximations to successfully perform the required biomolecular electrostatic calculations. The GUI also incorporates visualization tools to facilitate users pre- and post- analysis of structural and electrical properties of biomolecules.

Adsorption of soft and hard proteins onto OTCEs under the influence of an external electric field.

The adsorption behavior of hard and soft proteins under the effect of an external electric field was investigated by a combination of spectroscopic ellipsometry and molecular dynamics (MD) simulations. Optically transparent carbon electrodes (OTCE) were used as conductive, sorbent substrates. Lysozyme (LSZ) and ribonuclease A (RNase A) were selected as representative hard proteins, whereas myoglobin (Mb), α-lactalbumin (α-LAC), bovine serum albumin (BSA), glucose oxidase (GOx), and immunoglobulin G (IgG) were selected to represent soft proteins. In line with recent publications from our group, the experimental results revealed that while the adsorption of all investigated proteins can be enhanced by the potential applied to the electrode, the effect is more pronounced for hard proteins. In contrast with the incomplete monolayers formed at open-circuit potential, the application of +800 mV to the sorbent surface induced the formation of multiple layers of protein. These results suggest that this effect can be related to the intrinsic polarizability of the protein (induction of dipoles), the resulting surface accessible solvent area (SASA), and structural rearrangements induced upon the incorporation on the protein layer. The described experiments are critical to understand the relationship between the structure of proteins and their tendency to form (under electric stimulation) layers with thicknesses that greatly surpass those obtained at open-circuit conditions.

Biodirected synthesis and nanostructural characterization of anisotropic gold nanoparticles.

Gold nanoparticles with anisotropic structures have tunable absorption properties and diverse bioapplications as image contrast agents, plasmonics, and therapeutic-diagnostic materials. Amino acids with electrostatically charged side chains possess inner affinity for metal ions. Lysine (Lys) efficiently controlled the growing into star-shape nanoparticles with controlled narrow sizes (30-100 nm) and produced in high yields (85-95%). Anisotropic nanostructures showed tunable absorbance from UV to NIR range, with extraordinary colloidal stability (-26 to -42 mV) and surface-enhanced Raman scattering properties. Advanced electron microscopy characterization through ultra-high-resolution SEM, STEM, and HR-TEM confirmed the size, nanostructure, crystalline structure, and chemical composition. Molecular dynamics simulations revealed that Lys interacted preferentially with Au(I) through the -COOH group instead of their positive side chains with a binding free energy (BFE) of 3.4 kcal mol(-1). These highly monodisperse and colloidal stable anisotropic particles prepared with biocompatible compounds may be employed in biomedical applications.

Biomolecular electrostatics and solvation: a computational perspective.

An understanding of molecular interactions is essential for insight into biological systems at the molecular scale. Among the various components of molecular interactions, electrostatics are of special importance because of their long-range nature and their influence on polar or charged molecules, including water, aqueous ions, proteins, nucleic acids, carbohydrates, and membrane lipids. In particular, robust models of electrostatic interactions are essential for understanding the solvation properties of biomolecules and the effects of solvation upon biomolecular folding, binding, enzyme catalysis, and dynamics. Electrostatics, therefore, are of central importance to understanding biomolecular structure and modeling interactions within and among biological molecules. This review discusses the solvation of biomolecules with a computational biophysics view toward describing the phenomenon. While our main focus lies on the computational aspect of the models, we provide an overview of the basic elements of biomolecular solvation (e.g. solvent structure, polarization, ion binding, and non-polar behavior) in order to provide a background to understand the different types of solvation models.

Ionic asymmetry and solvent excluded volume effects on spherical electric double layers: a density functional approach.

In this article, we present a classical density functional theory for electrical double layers of spherical macroions that extends the capabilities of conventional approaches by accounting for electrostatic ion correlations, size asymmetry, and excluded volume effects. The approach is based on a recent approximation introduced by Hansen-Goos and Roth for the hard sphere excess free energy of inhomogeneous fluids [J. Chem. Phys. 124, 154506 (2006); Hansen-Goos and Roth, J. Phys.: Condens. Matter 18, 8413 (2006)]. It accounts for the proper and efficient description of the effects of ionic asymmetry and solvent excluded volume, especially at high ion concentrations and size asymmetry ratios including those observed in experimental studies. Additionally, we utilize a leading functional Taylor expansion approximation of the ion density profiles. In addition, we use the mean spherical approximation for multi-component charged hard sphere fluids to account for the electrostatic ion correlation effects. These approximations are implemented in our theoretical formulation into a suitable decomposition of the excess free energy which plays a key role in capturing the complex interplay between charge correlations and excluded volume effects. We perform Monte Carlo simulations in various scenarios to validate the proposed approach, obtaining a good compromise between accuracy and computational cost. We use the proposed computational approach to study the effects of ion size, ion size asymmetry, and solvent excluded volume on the ion profiles, integrated charge, mean electrostatic potential, and ionic coordination number around spherical macroions in various electrolyte mixtures. Our results show that both solvent hard sphere diameter and density play a dominant role in the distribution of ions around spherical macroions, mainly for experimental water molarity and size values where the counterion distribution is characterized by a tight binding to the macroion, similar to that predicted by the Stern model.

Excluded volume and ion-ion correlation effects on the ionic atmosphere around B-DNA: theory, simulations, and experiments.

The ionic atmosphere around a nucleic acid regulates its stability in aqueous salt solutions. One major source of complexity in biological activities involving nucleic acids arises from the strong influence of the surrounding ions and water molecules on their structural and thermodynamic properties. Here, we implement a classical density functional theory for cylindrical polyelectrolytes embedded in aqueous electrolytes containing explicit (neutral hard sphere) water molecules at experimental solvent concentrations. Our approach allows us to include ion correlations as well as solvent and ion excluded volume effects for studying the structural and thermodynamic properties of highly charged cylindrical polyelectrolytes. Several models of size and charge asymmetric mixtures of aqueous electrolytes at physiological concentrations are studied. Our results are in good agreement with Monte Carlo simulations. Our numerical calculations display significant differences in the ion density profiles for the different aqueous electrolyte models studied. However, similar results regarding the excess number of ions adsorbed to the B-DNA molecule are predicted by our theoretical approach for different aqueous electrolyte models. These findings suggest that ion counting experimental data should not be used alone to validate the performance of aqueous DNA-electrolyte models.

Theory of Weakly Polydisperse Cytoskeleton Filaments.

Cytoskeleton filaments have the extraordinary ability to change conformations dynamically in response to alterations of the number density of actins/tubulin, the number density and type of binding agents, and the electrolyte concentration. This property is crucial for eukaryotic cells to achieve specific biological functions in different cellular compartments. Conventional approaches to biopolymers' solution break down for cytoskeleton filaments because they entail several approximations to treat their polyelectrolyte and mechanical properties. In this article, we introduce a novel density functional theory for polydisperse, semiflexible cytoskeleton filaments. The approach accounts for the equilibrium polymerization kinetics, length and orientation filament distributions, as well as the electrostatic interaction between filaments and the electrolyte. This is essential for cytoskeleton polymerization in different cell compartments generating filaments of different lengths, sometimes long enough to become semiflexible. We characterized the thermodynamics properties of actin filaments in electrolyte aqueous solutions. We calculated the free energy, pressure, chemical potential, and second virial coefficient for each filament conformation. We also calculated the phase diagram of actin filaments' solution and compared with the corresponding results in in vitro experiments.

Molecular structure study on the polyelectrolyte properties of actin filaments.

An accurate characterization of the polyelectrolyte properties of actin filaments might provide a deeper understanding of the fundamental mechanisms governing the intracellular ionic wave packet propagation in neurons. Infinitely long cylindrical models for actin filaments and approximate electrochemical theories for the electrolyte solutions were recently used to characterize these properties in in vitro and intracellular conditions. This article uses a molecular structure model for actin filaments to investigate the impact of roughness and finite size on the mean electrical potential, ionic density distributions, currents, and conductivities. We solved the electrochemical theories numerically without further approximations. Our findings bring new insights into the electrochemical interactions between a filament's irregular surface charge density and the surrounding medium. The irregular shape of the filament structure model generated pockets, or hot spots, where the current density reached higher or lower magnitudes than those in neighboring areas throughout the filament surface. It also revealed the formation of a well-defined asymmetric electrical double layer with a thickness larger than that commonly used for symmetric models.

CACPPAF, a COMSOL application to characterize polyelectrolyte properties of actin filaments.

We present an interactive COMSOL web application that allows both expert and non-expert users to numerically evaluate the electric potential, ionic concentration distribution, velocity profile, and ionic current along a molecular structure surface characterizing actin filaments. This online computational and visualization tool runs on a high performance server (http://marucholab.physics.utsa.edu:2036), that enables users to perform multiple analyses and comparisons without compromising computational resources. As a unique feature, the multiphysics formulation accounts for the filament surface roughness, the finite filament size, and the ionic condensation, providing a deeper understanding of the electrochemical phenomena taking place at the interface between the irregular charged shape of the filament and its biological environment. Overall, the interactive component allows investigators to characterize polyelectrolyte properties of healthy and abnormal actin filaments in physiological and pathological conditions.

Hydrodynamic and Polyelectrolyte Properties of Actin Filaments: Theory and Experiments.

Actin filament's polyelectrolyte and hydrodynamic properties, their interactions with the biological environment, and external force fields play an essential role in their biological activities in eukaryotic cellular processes. In this article, we introduce a unique approach that combines dynamics and electrophoresis light-scattering experiments, an extended semiflexible worm-like chain model, and an asymmetric polymer length distribution theory to characterize the polyelectrolyte and hydrodynamic properties of actin filaments in aqueous electrolyte solutions. A fitting approach was used to optimize the theories and filament models for hydrodynamic conditions. We used the same sample and experimental conditions and considered several g-actin and polymerization buffers to elucidate the impact of their chemical composition, reducing agents, pH values, and ionic strengths on the filament translational diffusion coefficient, electrophoretic mobility, structure factor, asymmetric length distribution, effective filament diameter, electric charge, zeta potential, and semiflexibility. Compared to those values obtained from molecular structure models, our results revealed a lower value of the effective G-actin charge and a more significant value of the effective filament diameter due to the formation of the double layer of the electrolyte surrounding the filaments. Contrary to the data usually reported from electron micrographs, the lower values of our results for the persistence length and average contour filament length agree with the significant difference in the association rates at the filament ends that shift to sub-micro lengths, which is the maximum of the length distribution.

In vitro Preparation of Homogenous Actin Filaments for Dynamic and Electrophoretic Light Scattering Measurements.

Actin filaments are essential for various biological activities in eukaryotic cellular processes. Available in vitro experimental data on these systems often lack details and information on sample preparation protocols and experimental techniques, leading to unreproducible results. Additionally, different experimental techniques and polymerization buffers provide different, sometimes contradictory results on the properties of these systems, making it substantially difficult to gather meaningful data and conclusive information from them. This article presents a robust, accurate, detailed polymerization protocol to prepare high-quality actin filament samples for light scattering experiments. It has been shown to provide unicity and consistency in preparing stable, dispersed, aggregates-free, homogenous actin filament samples that could benefit many other scientific research groups currently working in the field. To develop the protocol, we used conventional actin buffers in physiological conditions. However, it can easily be adapted to prepare samples using other buffers and biological fluids. This protocol yielded reproducible results on essential actin filament parameters such as the translational diffusion coefficient and electrophoretic mobility. Overall, suitable modifications of the proposed experimental method could generate accurate, reproducible light scattering results on other highly charged anionic filaments commonly found in biological cells (e.g., microtubules, DNAs, RNAs, or filamentous viruses). This protocol was validated in: Polymers (2022), DOI: 10.3390/polym14122438 Graphical abstract.

Java application for cytoskeleton filament characterization (JACFC).

JACFC is a Java web application (http://neuronanobiophysics.utsa.edu/) that provides both experts and non-experts in the field suitable tools for elucidating the molecular mechanisms modulating the electrical signal propagation, stability, and bundle formation of microtubules and actin filaments under different molecular (wild type, isoforms, mutants) and environmental (physiological and pathological) conditions. This acknowledgment might reveal the potential role of cytoskeleton filaments in neuronal activities, including molecular-level processing of information and neural regeneration. Molecular understanding of the polyelectrolyte properties of bionanowires, is also crucial for development of reliability, highly functioning small devices with biotechnological applications such as bionanosensors and computing bionanoprocessors.

The Self-Adaptation Ability of Zinc Oxide Nanoparticles Enables Reliable Cancer Treatments.

Optimal procedures for reliable anti-cancer treatments involve the systematic delivery of zinc oxide nanoparticles, which spread through the circulatory system. The success of these procedures may largely depend on the NPs' ability of self-adapting their physicochemical properties to overcome the different challenges facing at each stage on its way to the interior of a cancerous cell. In this article, we combine a multiscale approach, a unique nanoparticle model, and available experimental data to characterize the behavior of zinc oxide nanoparticles under different vessels rheology, pH levels, and biological environments. We investigate their ability to prevent aggregation, allow prolonged circulation time in the bloodstream, avoid clearance, conduct themselves through the capillarity system to reach damaged tissues, and selectively approach to target cancerous cells. Our results show that non-functionalized spherical zinc oxide nanoparticles with surface density N = 5.89 × 10-6 mol/m2, protonation and deprotonation rates pKa = 10.9 and pKb = -5.5, and NP size in the range of 20-50 nm are the most effective, smart anti-cancer agents for biomedical treatments.

A multi-scale approach to describe electrical impulses propagating along actin filaments in both intracellular and in vitro conditions.

An accurate and efficient characterization of the polyelectrolyte properties for cytoskeleton filaments are key to the molecular understanding of electrical signal propagation, bundle and network formation, as well as their potential nanotechnological applications. In this article, we introduce an innovative multi-scale approach able to account for the atomistic details of a protein molecular structure, its biological environment, and their impact on electrical impulses propagating along wild type Actin filaments. The formulation includes non trivial contributions to the ionic electrical conductivity and capacitance coming from the diffuse part of the electrical double layer of G-actins. We utilize this monomer characterization in a nonlinear inhomogeneous transmission line prototype model to account for the monomer-monomer interactions, dissipation and damping perturbations along the filament length. A novel, simple, accurate, approximate analytic expression has been obtained for the transmission line model. Our results reveal the propagation of electrical signal impulses in the form of solitons for the range of voltage stimulus and electrolyte solutions typically present for intracellular and in-vitro conditions. The approach predicts a lower electrical conductivity with higher linear capacitance and nonlinear accumulation of charge for intracellular conditions. Our results show a significant influence of the voltage input on the electrical impulse shape, attenuation and kern propagation velocity. The filament is able to sustain the soliton propagation at almost constant kern velocity for the in-vitro condition, whereas the intracellular condition displays a remarkable deceleration. Additionally, the solitons are narrower and travel faster at higher voltage input. As a unique feature, this multi-scale theory is able to account for molecular structure conformation (mutation) and biological environment (protonations/deprotonations) changes often present in pathological conditions. It is also applicable to other highly charged rod-like polyelectrolytes with relevance in biomedicine and biophysics.

Polar-solvation classical density-functional theory for electrolyte aqueous solutions near a wall.

A precise description of the structural and dielectric properties of liquid water is critical to understanding the physicochemical properties of solutes in electrolyte solutions. In this article, a mixture of ionic and dipolar hard spheres is considered to account for water crowding and polarization effects on ionic electrical double layers near a uniformly charged hard wall. As a unique feature, solvent hard spheres carrying a dipole at their centers were used to model water molecules at experimentally known concentration, molecule size, and dipolar moment. The equilibrium ionic and dipole density profiles of this electrolyte aqueous model were calculated using a polar-solvation classical density-functional theory (PSCDFT). These profiles were used to calculate the charge density distribution, water polarization, dielectric permittivity function, and mean electric potential profiles as well as differential capacitance, excess adsorptions, and wall-fluid surface tension. These results were compared with those corresponding to the pure dipolar model and unpolar primitive solvent model of electrolyte aqueous solutions to understand the role that water crowding and polarization effects play on the structural and thermodynamic properties of these systems. Overall, PSCDFT predictions are in agreement with available experimental data.

Ion-ion correlation, solvent excluded volume and pH effects on physicochemical properties of spherical oxide nanoparticles.

One major source of complexity in the implementation of nanoparticles in aqueous electrolytes arises from the strong influence that biological environments has on their physicochemical properties. A key parameter for understanding the molecular mechanisms governing the physicochemical properties of nanoparticles is the formation of the surface charge density. In this article, we present an efficient and accurate approach that combines a recently introduced classical solvation density functional theory for spherical electrical double layers with a surface complexation model to account for ion-ion correlation and excluded volume effects on the surface titration of spherical nanoparticles. We apply the proposed computational approach to account for the charge-regulated mechanisms on the surface chemistry of spherical silica (SiO2) nanoparticles. We analyze the effects of the nanoparticle size, as well as pH level and electrolyte concentration of the aqueous solution on the nanoparticle's surface charge density and Zeta potential. We validate our predictions for 580Å and 200Å nanoparticles immersed in acid, neutral and alkaline mono-valent aqueous electrolyte solutions against experimental data. Our results on mono-valent electrolyte show that the excluded volume and ion-ion correlations contribute significantly to the surface charge density and Zeta potential of the nanoparticle at high electrolyte concentration and pH levels, where the solvent crowding effects and electrostatic screening have shown a profound influence on the protonation/deprotonation reactions at the liquid/solute interface. The success of this approach in describing physicochemical properties of silica nanoparticles supports its broader application to study other spherical metal oxide nanoparticles.