Free Energy Of Aggregation Research Articles

Wild-Type α-Synuclein Structure and Aggregation: A Comprehensive Coarse-Grained and All-Atom Molecular Dynamics Study.

α-Synuclein (α-syn) is a 140 amino acid intrinsically disordered protein (IDP) and the primary component of cytotoxic oligomers implicated in the etiology of Parkinson's disease (PD). While IDPs lack a stable three-dimensional structure, they sample a heterogeneous ensemble of conformations that can, in principle, be assessed through molecular dynamics simulations. However, describing the structure and aggregation of large IDPs is challenging due to force field (FF) accuracy and sampling limitations. To cope with the latter, coarse-grained (CG) FFs emerge as a potential alternative at the expense of atomic detail loss. Whereas CG models can accurately describe the structure of the monomer, less is known about aggregation. The latter is key for assessing aggregation pathways and designing aggregation inhibitor drugs. Herein, we investigate the structure and dynamics of α-syn using different resolution CG (Martini3 and Sirah2) and all-atom (Amber99sb and Charmm36m) FFs to gain insight into the differences and resemblances between these models. The dependence of the magnitude of protein-water interactions and the putative need for enhanced sampling (replica exchange) methods in CG simulations are analyzed to distinguish between force field accuracy and sampling limitations. The stability of the CG models of an α-syn fibril was also investigated. Additionally, α-syn aggregation was studied through umbrella sampling for the CG models and CG/all-atom models for an 11-mer peptide (NACore) from an amyloidogenic domain of α-syn. Our results show that despite the α-syn structures of Martini3 and Sirah2 with enhanced protein-water interactions being similar, major differences exist concerning aggregation. The Martini3 fibril is not stable, and the binding free energy of α-syn and NACore is positive, opposite to Sirah2. Sirah2 peptides in a zwitterionic form, in turn, display termini interactions that are too strong, resulting in end-to-end orientation. Sirah2, with enhanced protein-water interactions and neutral termini, provides, however, a peptide aggregation free energy profile similar to that found with all-atom models. Overall, we find that Sirah2 with enhanced protein-water interactions is suitable for studying protein-protein and protein-drug aggregation.

Structure Regulation of Sodium Ion on Nanosilica Growth Visualized Using 29Si Nuclear Magnetic Resonance Spectroscopy

Understanding the action mechanism of sodium ions in sodium silicate solutions is necessary for the synthesis of nanosilica. The microstructure of sodium silicate solutions with SiO2:Na2O ratios ranging from 2 to 4 was characterized by 29Si nuclear magnetic resonance spectroscopy, and the magnetic shielding tensor of the nuclear magnetic field was calculated using the density functional theory. Sodium ions contribute significantly to the magnetic shielding tensor, thereby playing a key role in the structural evolution of sodium silicate solution species. Wave function analysis was used to further study the mechanism of action of sodium ions. Theoretical calculation results show that Na not only affects the magnetic shielding and regulates the splitting and change of NMR peaks but also regulates the aggregation-free energy and growth morphology of silica nanoparticles. Thus, the structural regulation of sodium ions on nanosilica growth and aggregation was proposed. Magnetic shielding caused by partial symmetry disappears with the reduction of sodium ions in the system, resulting in uniform magnetic shielding. Meanwhile, the anisotropic aggregation free energy of microscopic particles tends to be isotropically distributed, resulting in the spherical growth tendency of the nanosilica particles. Small-angle X-ray scattering and transmission electron microscopy were used to verify these conclusions. In this work, we adopted the leading quantum chemical computational methods with advanced computer technology and quantum chemical methods to research the microscopic effect of sodium ions during nanosilica growth, thereby overcoming the limitations of the analytical experience and paradigm established with traditional organic chemistry and providing important theoretical reference value for the field of spectral systems and characterization measurement methods. At the same time, the reasonable mechanism of action is proposed, which greatly expands the product application field of nanosilica.

Exploring the Interplay between Disordered and Ordered Oligomer Channels on the Aggregation Energy Landscapes of α-Synuclein.

The abnormal aggregation of α-synulcein is associated with multiple neurodegenerative diseases such as Parkinson's disease. The hydrophobic non-amyloid component (NAC) region of α-synuclein comprises the core of the fibril in vitro and in vivo. In this work, we study the aggregation landscape of the hydrophobic NAC region of α-synuclein using a transferrable coarse-grained force field, the associative memory water-mediated structure, and energy model (AWSEM). Using structural similarity, we can group metastable states on the free energy landscape of aggregation into three types of oligomers: disordered oligomers, prefibrillar oligomers with disordered tips, and ordered prefibrillar oligomers. The prefibrillar oligomers with disordered tips have more in-register parallel β strands than do the fully disordered oligomers but have fewer in-register parallel β strands than the ordered prefibrillar oligomers. Along with the ordered prefibrillar species, the disordered oligomeric states dominate at small oligomer sizes while the prefibrillar species with disordered tips thermodynamically dominate with the growth of oligomers. The topology of the aggregation landscape and observations in simulations suggest there is backtracking between ordered prefibrillar oligomers and other kinds of oligomers as the aggregation proceeds. The significant structural differences between the ordered prefibrillar oligomers and the disordered oligomers support the idea that the growth of these two kinds of oligomers involves kinetically independent parallel pathways. In contrast, the overall structural similarity between the fully ordered prefibrillar oligomers and the prefibrillar oligomers with disordered tips implies that two channels can interconvert on slower time scales. We also evaluate the effects of phosphorylation on the aggregation free energy landscape using statistical mechanical perturbation theory.

Star-type melamine based conjugated carboxy functionalized porphyrin trimer for DSSCs: An efficient approach to clean, aggregation free and true energy generation

A novel, π-conjugated melamine-based trimeric porphyrin dye with serving nine carboxylate linker groups has been prepared to use as a panchromatic dye for application in dye-sensitized solar cells (DSSCs). The star-shaped trimer was characterized by using Proton Nuclear Magnetic Resonance (NMR) Spectroscopy, Carbon Nuclear Magnetic Resonance Spectroscopy (CMR), Fourier Transformed Infrared Spectroscopy (FT-IR), UV-VIS Absorption Spectroscopy, Thermo-gravimetric analysis (TGA), Cyclic Voltammetry (CV) and Electrochemical Impedance Studies (EIS). CV studies revealed frontiers energy levels at −5.654 (HOMO) and −3.879 eV (LUMO) versus vacuum. The optical band gap evolved via absorption spectra measurements was found to be 1.49 eV. A planar perfect conjugation among three porphyrins sets up multiple push-pull communication and lowers the bandgap, while nine carboxylate linkers cover-up TiO2 surface effectively leading to better electronic dynamics. The DSSC set up using iodide-based redox couples forms a simple, stable, additive-free, truly energy generating device with 7.1% conversion efficiency, the highest among trimeric porphyrin category.

Performance of Asphaltic Concrete Incorporating Fly Ash under Low Temperature

One of the most common asphalt concrete pavement distresses is low temperature cracking, also known as thermal cracking. Characterizations of low temperature cracking and formulation for pavement design have taken a lot of effort. Asphalt binder has viscoelastic behaviour, so asphalt mixture behaviour changes as the temperature changes. At high and low temperatures, the asphalt binder shows viscoelastic plastic behaviour and elastic behaviour. Low temperature cracks that grow day by day due to the movement of vehicles are the most significant pavement cracks caused by cold climates. It needs early and premature repairs to build and expand low temperature cracks. The aim of this research is to perform Low Temperature Cracking analysis of asphalt materials (laboratory and analytical assessment), in light of the latest update of binder cracking temperature. The role of basic material properties in low-temperature cracking was studied in this work. As a result, statistical analysis in the cohesive failure condition revealed that the asphalt mixture aggregate's free energy was ineffective in this cohesion failure. Fly ash had been used in the other type of asphalt mixture. It was proven that the addition of fly ash as an additive can improves the low temperature resistance of the asphalt mix. The binder with 60/70 penetration grade was used. The different amount of fly ash (0%, 1%, 3% and 5%) was added to the asphalt mixture. Marshall Stability and flow, resilient modulus and dynamic creep were carried out to investigate the mechanisms of cracking at low temperature. From the results obtained, there are significant effect comes from the addition of the fly ash. The result show that the addition of 5% fly ash produce the best outcomes for the density, stability, stiffness, resilient modulus and dynamic creep. Thus, it can conclude that the existence of fly ash in the mixture is able to enhance the mechanical performance of the AC14 dense-graded asphalt.

Multi-Scale Modelling of Aggregation of TiO2 Nanoparticle Suspensions in Water.

Titanium dioxide nanoparticles have risen concerns about their possible toxicity and the European Food Safety Authority recently banned the use of TiO2 nano-additive in food products. Following the intent of relating nanomaterials atomic structure with their toxicity without having to conduct large-scale experiments on living organisms, we investigate the aggregation of titanium dioxide nanoparticles using a multi-scale technique: starting from ab initio Density Functional Theory to get an accurate determination of the energetics and electronic structure, we switch to classical Molecular Dynamics simulations to calculate the Potential of Mean Force for the connection of two identical nanoparticles in water; the fitting of the latter by a set of mathematical equations is the key for the upscale. Lastly, we perform Brownian Dynamics simulations where each nanoparticle is a spherical bead. This coarsening strategy allows studying the aggregation of a few thousand nanoparticles. Applying this novel procedure, we find three new molecular descriptors, namely, the aggregation free energy and two numerical parameters used to correct the observed deviation from the aggregation kinetics described by the Smoluchowski theory. Ultimately, molecular descriptors can be fed into QSAR models to predict the toxicity of a material knowing its physicochemical properties, enabling safe design strategies.

Simple analytical theory for micelles with widespread radial distribution of charged heads

Modeling aggregation of ionic micelles in solution is an important task that has been attracting attention for years. The molecular-thermodynamic micellization models describe the electrostatic interactions within the Poisson-Boltzmann theory that does not take into account fluctuations of the surfactant heads in the micelle. In this work we apply the statistical field theory to spherical micelles where the charged heads of surfactant molecules undergo fluctuations in the diffuse coronae. From this theory, a simple equation is derived for the electrostatic contribution to the standard free energy of aggregation. The results from the new theory are compared with the numerical results and analytical approximations of the Poisson-Boltzmann theory for the spheres of varying charge and curvature in the ranges relevant to micelles and over a broad interval of solution salinity. The new electrostatic free energy term is employed in the classical molecular-thermodynamic model to describe spherical micelles in the aqueous solution of ionic surfactant with added salt. We introduce an empirical correction that takes into account the effect of fluctuations on the hydrophobic part of the aggregation free energy. Modeling aggregation equilibrium for the spherical SDS micelles in the aqueous solution of salt, we illustrate the performance of the new theory. We compare our results with the structural MD-data and experimental hydrodynamic radii to show that our model with the fluctuating surfactant heads can reflect a realistic picture of the micellar structure and gives reasonable size-estimates for the spherical ionic micelles if proper charge distributions are considered.

Cationic Imidazolium Polythiophenes: Effects of Imidazolium-Methylation on Solution Concentration-Driven Aggregation and Surface Free Energy of Films Processed from Solvents with Different Polarity.

Cationic imidazolium-functionalized polythiophenes with single- or double-methylation of the imidazolium ring were used to study the impact of imidazolium-methylation on (i) the solution concentration-driven aggregation in the presence of paramagnetic probes with different ionic and hydrophobic constituents and (ii) their surface free energy (SFE) as spin-coated films deposited on plasma-activated glass. Electron paramagnetic resonance spectroscopy shows that the differences in film structuration between the polymers with different methylations originate from the early stages of aggregation. In the solid state, higher degree of imidazolium-methylation generates smaller values of total SFE, γS, (by around 2 mN/m), which could be relevant in optoelectronic applications. Methylation also causes a decrease in the polar contribution of γS (γSp), suggesting that methylation decreases the polar nature of the imidazolium ring, probably due to the blocking of its H-bonding capabilities. The values of γS obtained in the present work are similar to the values obtained for doped films of neutral conjugated polymers, such as polyaniline, poly(3-hexylthiophene), and polypyrrole. However, imidazolium-polythiophenes generate films with a larger predominance of the dispersive component of γS (γSd), probably due to the motion restriction in the ionic functionalities in a conjugated polyelectrolyte, in comparison to regular dopants. The presence of 1,4-dioxane increases γSp, especially, in the polymer with larger imidazolium-methylation (and therefore unable to interact through H-bonding), probably by a decrease of the imidazolium–glass interactions. Singly-methylated imidazolium polythiophenes have been applied as electrode selective (“buffer”) interlayers in conventional and inverted organic solar cells, improving their performance. However, clear structure–function guidelines are still needed for designing high-performance polythiophene-based interlayer materials. Therefore, the information reported in this work could be useful for such applications.

Spectrometric, Thermodynamic, pH Metric and Viscometric Studies on the Binding of TEALS as Surfactant with Albumin as Biopolymer

Background:: Since the interactions of small anions with protein are very important in their transportation and distribution processes in biological systems, it is helpful to study these interactions to understand the nature of the transportation and distribution processes. Therefore, it is aimed to study the interaction of albumin with surfactant molecule by different physical methods. Objective:: Present work attempts to work on assessing the structure, characterization of the surfactants as TEALS (tri-ethanalamine lauryl sulphate) binding sites, with albumin involved in various process of living being are discussed. Method:: The binding of surfactant TEALS to egg protein has been studied at different pH values and temperatures by spectrophotometric and equilibrium dialysis methods. The binding data were found to be pH and temperature dependent. The binding data studied by the absorbance method, were found approximately identical with those obtained from the equilibrium dialysis method. Results:: The association constants and the number of binding sites were calculated from Scatchard plots and found to be at maximum at lower pH and at lower temperature. The free energy of the combining sites was lowest at higher pH and highest at low pH. Therefore, a lower temperature and a lower pH offered more sites in the protein molecule for interaction with surfactant. The ΔG (free energies of aggregation) associated with the binding interaction of the surfactants and protein were calculated. The negative values of the ΔG confirm the feasibility of interaction between the surfactant and protein. All the observations recorded in this paper indicate that the TEALS has a good affinity of binding with egg protein and the number of binding sites is dependent on various physical and chemical factors. Conclusion:: On the basis of the results of the experiments which were conducted to examine the interaction between anionic surfactant and protein by measuring the various parameters of the solutions, it is concluded that the interaction of surfactant and protein gives an idea of fundamental understanding of the structure of surfactant-protein complex and their practical applications in every field.

Effect of gelatin protein on self-association behavior of sodium salt of ibuprofen drug in urea solution

Herein, multi-techniques approaches such as conductometry, tensiometry, fluorometry, and FT-IR were engaged to evaluate the interaction between sodium salt of ibuprofen (IB) and gelatin (GN) at 298.15 K in 250 mmol·kg−1 urea (UR) solution. The current employed drug is used for relief of pain. The employed IB drug interacts through GN protein like the interaction between surfactants and polymers. It is clear that the graph obtained from the conductometric and tensiometry methods shows two clear breaks. Urea acts as water structure breaker and their presence in solution enhance in surface charge of aggregates occurs. The obtained first break spot is labeled critical aggregation concentration (cc) which is quit beneath the usual critical micelle concentration (cmc) besides this the subsequently break spot denotes second one is regarded as polymer saturation point (pp) and this akin to cmc. The interaction between IB and GN in UR solution increases as concentration of protein increases in the solution mixtures as clear from their obtained cc value because the value of cc reduces through enhancing the concentration of GN (%w/v), in spite of this the value of pp value increases with increase in concentration of GN means more drug needed for complete saturation of binding site of protein. In UR solution, the Gibbs free energy of micellization (ΔGmic) for singular IB was achieved negative exploring that micellization process is spontaneous in nature. The other different evaluated thermodynamic parameters such as free energy of aggregation (ΔGagg), free energy of transfer (ΔGt), etc. were found in favor of interaction between IB and GN. Fluorometry technique was utilized to find out the various parameters such as micropolarity, aggregation numbers (Nagg), etc. to verify the interaction amongst studied constituents and with the interaction between them were also assessed by FT-IR study.

Investigation of aggregation behavior of ibuprofen sodium drug under the influence of gelatin protein and salt

The interaction of amphiphilic drug ibuprofen sodium salt (IBS) and gelatin (GT) protein have evaluated in the current system by means of conductometric, tensiometric and fluorometric techniques in aqueous as well as in aqueous electrolytes solutions at 298.15 K. IBS is utilized as an analgesic, an antipyretic and anti-inflammatory drug. Akin to surfactants and polymers interaction drug also interacts through gelatin. For that reason, in the present study, we have evaluated the drug IBS and gelatin (GT) interaction by means of conductimetry, tensiometry as fluorometry in aqueous along with in occurrence of additive (sodium chloride (NaCl)) at 298.15 K. From the graphs of specific conductivity against IBS concentration in case of conductivity and from the plots of surface tension (γ) vs. log IBS concentration, two break point was achieved in the occurrence of GT in absence and the presence of additives. The achieved primary cut-off point is entitled critical aggregation concentration (cc) that obtained lower than the characteristic critical micelle concentration (cmc) and the attained a subsequent cut-off point means the second one is entitled polymer saturation point (pp) i.e. resembling cmc. The interaction amongst IBS and GT occurs as a result of the well formation of the surface active complex by drug and GT as revealed via lessening of γ of gelatin solution through the addition of IBS in all different media. NaCl increases the interaction of IBS-GT mixtures. The achieved cc value of drug and gelatin mixtures reduce via raising the GT concentration (%w/v), while their pp value enhances viewing the clear interaction amid IBS and GT. Free energies of aggregation (ΔGagg) along with micellization (ΔGmic) were also assessed and discussed. Fluorescence spectroscopy was employed to evaluate the aggregation numbers (Nagg) of IBS and IBS-GT mixtures in the absence and occurrence of additive.

Thermodynamic Characterization of the Dimerization of an Anionic Perylene Bisimide Dye Using Molecular Simulation

The thermodynamic signature of dimerization of an anionic di(glycyl) perylene bisimide derivative in aqueous solution is characterized using molecular dynamics simulations in explicit solvent with the aim of determining the impact of temperature, pressure, and solvent composition on the free energy of aggregation and its enthalpic and entropic contributions. The change in free energy varies only weakly with temperature independent of whether the solvent consists of pure water, an aqueous ethanol/water mixture, or an aqueous solution of sodium chloride. In agreement with experimental findings, the addition of ethanol weakens the interactions between the solute molecules, whereas the addition of sodium chloride leads to more stable aggregates. The temperature dependence of the potential of mean force can be accurately described using a simple expression derived from thermodynamic perturbation theory of first order. Molecular driving forces are discussed in terms of solute–solute and solute–solvent interactions.

The Interaction and Thermodynamic Studies on the Binding of Congo Red Dye with Collagen Protein by Polarographic and Equilibrium Dialysis Techniques

Abstract The survey of the existing literature revealed that the binding of Molybdenum, Vanadium, Zinc, Cadmium, Copper, Nickel and Cobalt with the protein is well known but no binding studies of Congo red molecules with collagen are reported. With a view to extend the existed knowledge of ecological nature of dye-protein system, it was thought of interest to investigate of properties of dye-protein mixture. The binding of Congo red dye has been studied with collagen protein using polarographic and equilibrium dialysis techniques. The intrinsic association constants and the number of binding sites have been calculated from Scatchard plots. The effect of pH on these constants was studied at pH 5.57, 7.50, 9.50 by polarographic technique and it was found that these values were decreased with increasing pH. The effect of pH was found to be similar by equilibrium dialysis technique. The values of different thermodynamic parameters have been reported. The free energies of aggregation, ΔG associated with the binding interaction of the dyes and protein were calculated. The negative values of the ΔG confirm the feasibility of interaction between the dye and protein.

On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation.

Protein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic and hydrophobic interactions mediated by water. An impressive manifestation of the importance of this balance concerns the human hemoglobin (HbA) mutant, HbS (sickle cell Hb), where a single substitution at the 6th position of HbA β-chains, from glutamic acid to valine, causes the polymerization of deoxygenated HbS (deoxy-HbS), responsible for SCD. HbS polymerization is believed to occur via a double nucleation mechanism initiated by the formation of HbS fibers (homogeneous nucleation), followed by fiber growth. Furthermore, it was proposed that homogeneous nucleation proceeds through a two-step mechanism, where metastable dense clusters play the role of nucleation precursors. Thus, hindering or delaying the formation of such precursors could represent a potential SCD therapeutic route. Here, we study, through molecular dynamics, the binding free energy and protein-protein contacts involved in the deoxy-HbS dimer aggregation and stabilization process. A binding free energy of ∼-14.0 ± 1 kcal/mol is estimated from a one-dimensional potential of mean force. Analysis of protein-protein interactions shows that both electrostatic and van der Waals interactions play an important role on the aggregation of HbS. With respect to the former, our results indicate that aggregation is largely favored by the formation of salt bridges (SB), mostly, Lys-Glu, Lys-Asp, and Heme-Lys SB, which outweigh electrostatic repulsions involving similar residues. Thus, our results suggest that a potential antisickling drug could be one with the ability to weaken or hinder the formation of a few SB between carboxylate and ammonium groups.

Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1-42) and Amyloid Beta(1-40).

Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid-β protein (1-42) and amyloid-β protein (1-40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of Aβ42 is more downhill, with a computed solubility that is about 10 times smaller than that of Aβ40. At a concentration of 40 μM, the clear free energy barrier between the pre-fibrillar tetramer form and the fibrillar pentamer in the Aβ40 aggregation landscape disappears for Aβ42, suggesting that the Aβ42 tetramer has a more diverse structural range. To further compare the landscapes, we develop a cluster analysis based on the structural similarity between configurations and use it to construct an oligomerization map that captures the paths of easy interconversion between different but structurally similar states of oligomers for both species. A taxonomy of the oligomer species based on β-sheet stacking topologies is proposed. The comparison of the two oligomerization maps highlights several key differences in the landscapes that can be attributed to the two additional C-terminal residues that Aβ40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for Aβ42 relative to Aβ40, and greatly facilitate the conversion from pre-fibrillar trimers to fibrillar tetramers.

The Aggregation Free Energy Landscapes of Polyglutamine Repeats.

Aggregates of proteins containing polyglutamine (polyQ) repeats are strongly associated with several neurodegenerative diseases. The length of the repeats correlates with the severity of the disease. Previous studies have shown that pure polyQ peptides aggregate by nucleated growth polymerization and that the size of the critical nucleus (n*) decreases from tetrameric to dimeric and monomeric as length increases from Q18 to Q26. Why the critical nucleus size changes with repeat-length has been unclear. Using the associative memory, water-mediated, structure and energy model, we construct the aggregation free energy landscapes for polyQ peptides of different repeat-lengths. These studies show that the monomer of the shorter repeat-length (Q20) prefers an extended conformation and that its aggregation indeed has a trimeric nucleus (n* ∼ 3), while a longer repeat-length monomer (Q30) prefers a β-hairpin conformation which then aggregates in a downhill fashion at 0.1 mM. For an intermediate length peptide (Q26), there is an equal preference for hairpin and extended forms in the monomer which leads to a mixed inhomogeneous nucleation mechanism for fibrils. The predicted changes of monomeric structure and nucleation mechanism are confirmed by studying the aggregation free energy profile for a polyglutamine repeat with site-specific PG mutations that favor the hairpin form, giving results in harmony with experiments on this system.

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1-40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer's disease.

Multi-shell model of ion-induced nucleic acid condensation

We present a semi-quantitative model of condensation of short nucleic acid (NA) duplexes induced by trivalent cobalt(iii) hexammine (CoHex) ions. The model is based on partitioning of bound counterion distribution around single NA duplex into "external" and "internal" ion binding shells distinguished by the proximity to duplex helical axis. In the aggregated phase the shells overlap, which leads to significantly increased attraction of CoHex ions in these overlaps with the neighboring duplexes. The duplex aggregationfree energy is decomposed into attractive and repulsive components in such a way that they can be represented by simple analytical expressions with parameters derived from molecular dynamic simulations and numerical solutions of Poisson equation. The attractive term depends on the fractions of bound ions in the overlapping shells and affinity of CoHex to the "external" shell of nearly neutralized duplex. The repulsive components of the free energy are duplex configurational entropy loss upon the aggregation and the electrostatic repulsion of the duplexes that remains after neutralization by bound CoHex ions. The estimates of the aggregationfree energy are consistent with the experimental range of NA duplex condensation propensities, including the unusually poor condensation of RNA structures and subtle sequence effects upon DNAcondensation. The model predicts that, in contrast to DNA, RNA duplexes may condense into tighter packed aggregates with a higher degree of duplex neutralization. An appreciable CoHex mediated RNA-RNA attraction requires closer inter-duplex separation to engage CoHex ions (bound mostly in the "internal" shell of RNA) into short-range attractive interactions. The model also predicts that longer NA fragments will condense more readily than shorter ones. The ability of this model to explain experimentally observed trends in NAcondensation lends support to proposed NAcondensation picture based on the multivalent "ion binding shells."

Thermodynamic properties of the aggregation behavior of a dicationic ionic liquid determined by different methods

Abstract The temperature effect on the aggregation of the IL 3,3′-(octane-1,8-diyl)bis(1-methyl-1H-imidazol-3-ium)bromide ([BisOct(MIM)2]Br2) in aqueous solution was studied in order to determine the aggregation properties, thermodynamic aggregation parameters, and aggregate size. The aggregation was investigated via conductivity, surface tension, dynamic light scattering (DLS), and nuclear magnetic resonance (NMR). The critical aggregation concentration (CAC), free energy of aggregation (ΔG°agg), and ionization degree (α) increased significantly with the increase in temperature. It was observed that the aggregation mechanism of [BisOct(MIM)2]Br2 is governed primarily by the enthalpic factor (ΔH°agg). The entropy term (TΔS°agg) becomes relevant above 318.15 K. The free energy adsorption (ΔG°ads) data demonstrated good surfactant activity for the dicationic IL studied; however, this property decreased at higher temperatures.

A Proteome-Level Computational Biology Insight on Sequence Based Aggregation Propensity Profile of Human Hydrolase Structural Enzymes

With the advancement in proteomics and bioinformatics, it is paramount to predict the causes of aggregation in all Human Hydrolase Enzymes (HHE), which have more tendencies to aggregate. Protein aggregation is associated with manifold pathological and neurodegenerative diseases because of amyloid fibrillation. Physico-chemical factors responsible for aggregation were studied in details. The positional dependencies of amylogenic regions in active participation for aggregation in HHE were correlated and brought into limelight through this study. Novel deductions from several studies in this research revealed that helical regions in the N-Terminal amylogenic regions mainly contributed for aggregation in HHE, especially for the ones having acidic theoretical pI. The presence of aggregation-prone highly fluctuating amino acid residues mainly in N-Terminal amylogenic regions was also explored. Withal, mutational alterations in the active sites, that could reduce net aggregation propensity and free energy of folding of entire HHE family leading to better foldability and reduction in the chances for the neurodegenerative disorders to be caused were also discerned with supportive statistical significance. Keywords: Amylogenic regions, free energy of folding, folding rate, mutational alteration, protein aggregation.