Entropic Interactions Research Articles

Investigating effects of bridging water on the binding of neuraminidase−ligands using computational alanine scanning combined with interaction entropy method

Bridging water can form hydrogen bonds with protein and ligand, thus it plays an important role in the binding of protein and ligand. However, the detailed binding mechanism between bridging water and protein−ligand complexes is still unclear. In this study, the effect of bridging water on the binding of neuraminidase (NA) and two ligands (G20 and G28) was investigated using molecular dynamic (MD) simulations and computational alanine scanning combined with the newly developed interaction entropy method. The calculated binding free energy was consistent with the experimental value. Moreover, the rank of calculated binding free energy was in excellent agreement with the experimental rank. Computation analysis showed that the addition of bridging water was beneficial to the binding of NA and ligand, and remarkably enhanced the binding free energy. This is because the existence of bridging water leads to the enhancement in the energy of some residues. Therefore, the number of hot-spot residues also increases after considering bridging water. Our study identified that Leu134, Asp151, Arg152, Trp178, Ile222, Arg224, Glu227, Glu276, Glu277, Arg292 and Tyr406 were the key residues in the neuraminidase−ligand complex. Besides, hydrogen bond analysis showed that bridging water could regulate the hydrogen bond network, and thus could increase the number of hydrogen bonds. It is helpful for enhancing the stability of the complex and is one of the reasons for promoting their binding. These results provide directions and ideas for the design of more effective drugs against neuraminidase in the future.

Studies on the Complexation of Succinic Hydrazide with Copper Chloride Salt

The electrochemical behavior of the complexation between copper chloride salt and succinic hydrazide can be explained using cyclic voltammetric measurements. The complex is formed through the interaction with nitrogen and hydroxyl group or carbonyl group of succinic hydrazides. This interaction can be observed by decreasing in the height peak of current and measuring the (anodic/cathodic) shift of the potentials. All the solvation and thermodynamic parameters for the interaction of copper ions with succinic hydrazide as stability constant, Gibbs free energies, enthalpies and entropies of interaction were calculated. Finally, the activity of the formed complex was compared with the succinic hydrazide by comparing their effects on different types of gram-negative bacteria and fungi indicating high activity of the formed complex and its ability to be used in different medical applications.

Negativity of the Casimir Self-Entropy in Spherical Geometries.

It has been recognized for some time that, even for perfect conductors, the interaction Casimir entropy, due to quantum/thermal fluctuations, can be negative. This result was not considered problematic because it was thought that the self-entropies of the bodies would cancel this negative interaction entropy, yielding a total entropy that was positive. In fact, this cancellation seems not to occur. The positive self-entropy of a perfectly conducting sphere does indeed just cancel the negative interaction entropy of a system consisting of a perfectly conducting sphere and plate, but a model with weaker coupling in general possesses a regime where negative self-entropy appears. The physical meaning of this surprising result remains obscure. In this paper, we re-examine these issues, using improved physical and mathematical techniques, partly based on the Abel–Plana formula, and present numerical results for arbitrary temperatures and couplings, which exhibit the same remarkable features.

Crowding-Induced Spatial Organization of Gene Expression in Cell-Sized Vesicles

E. coli cells, which are commonly used to study gene expression, show membraneless organization of gene expression components within the cell. Cell-free expression systems are also widely used to study gene expression, but a major limitation is the lack of a means to spatially organize DNA plasmids and ribosomes to mimic the cellular environment. In this work, we used computer simulations to guide experimental efforts to control the spatial organization of DNA and ribosomes in cell-sized vesicles using macromolecular crowding. Using Brownian dynamics simulations of coarse-grained models of DNA plasmids and crowders, we showed that plasmids remain uniformly distributed at low levels of crowding but become strongly adsorbed at confining surfaces at high levels of crowding. These effects are due to entropic depletion interactions resulting from the presence of crowding molecules. We validated the simulation results experimentally by using fluorescently-labelled DNA plasmids and ribosomes in cell-sized vesicles at different concentrations of the macromolecular crowder Ficoll-70. Large crowder concentrations resulted in preferential localization of plasmids at the walls of the vesicle, while ribosomes remained uniformly distributed throughout the vesicle. We then used kinetic Monte Carlo simulations to study how protein production was affected by crowding-induced changes in spatial organization and diffusion. The localization of DNA to the wall resulted in lower protein abundance and a decrease in translational efficiency with an increase in system size. Experimentally, we tracked the dynamics of transcription and translation in crowded vesicles using a coupled mRNA/protein reporter technique. These results were consistent with results from simulations. We thus used computer simulations to design a cell-free experimental platform capable of spatial organization of gene expression components. This platform can be used to better understand the spatial control of gene expression in cells.

Thermodynamic interactions of micellar casein and oat β-glucan in a model food system

Oat β-glucan is a soluble dietary fiber and its consumption is associated with the reduction of coronary heart disease risk (21 CFR 101.81). Dairy and food formulations have been used to deliver β-glucan's health benefits to consumers, but the addition of β-glucan in dairy beverages can induce phase separation because of its thermodynamic incompatibility with micellar casein. Ten binary mixtures were developed with concentrations at 0.5–2% β-glucan and 0.75–6% casein to investigate the micellar casein–β-glucan interaction mechanism and evaluate the effect of biopolymer concentrations, thermal treatment, and ionic strength on these interactions. Pasteurization (73 °C/15 s) and retort sterilization (121 °C/5 min) were the two applied thermal treatments. Three dispersion media were used in the preparation of the binary mixtures: 5 mM potassium phosphate buffer, 171 mM NaCl in phosphate buffer, and milk permeate. Upon preparation, the samples were stored for 5 days at 4 °C and then centrifuged at 4000 rpm for 2 h. The phase diagrams showed that both thermal treatments increased the biopolymer compatibility and suspension stability. The thermally treated formulations exhibited smaller particle sizes, which explains the higher stability. Increasing ionic strength decreased the biopolymer compatibility and suspension stability and increased the particle sizes. Isothermal titration calorimetry (ITC) showed that the heat of binding was small indicating entropic biopolymer interactions. Confocal microscopy images illustrated the immiscibility of the two biopolymers showing the formation of two phases.

Predicting molecular isomerism of symmetrical and unsymmetrical N,N′-diphenyl formamidines in the solid-state: crystal structure, Hirshfeld surface analysis, pairwise interaction energy, and ΔHfusion and ΔSfusion correlations

Correlating molecular isomerism of N,N′-diphenylformamidine derivatives in the solid state with molecular pairwise interaction energies, experimental enthalpy and entropy of fusion.

Computational analysis of binding free energies, hotspots and the binding mechanism of Bcl-xL/Bcl-2 binding to Bad/Bax.

The anti-apoptotic proteins B-cell lymphoma-extra large (Bcl-xL) and B-cell lymphoma/leukemia-2 (Bcl-2) are members of the Bcl-2 protein family, and they play important roles in regulating apoptosis and cell cycle retardation. However, the binding mechanisms of Bcl-xL/Bcl-2 with their associated agonists, including Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax), are not well understood. In the present study, the recently developed interaction entropy approach was employed for the calculation of entropic contribution, and the computational alanine scanning method was used to identify the hot spot in the protein-protein interactions between Bcl-xL/Bcl-2 and Bad/Bax. The calculated binding free energies and their ranks for the four systems were in good agreement with the experimental results. Computational analysis shows that there are more hot-spot residues in the Bcl-xL/Bad complex than that in the Bcl-xL/Bax complex, leading to a stronger binding affinity in the former. It is interesting to find that the reason for the stronger binding affinity of Bcl-2 to Bad than to Bax is different for the Bcl-xL system. Although there are more hot-spot residues in the Bcl-2/Bax system than in the Bcl-2/Bad complex, there are also more negatively contributing residues in the Bcl-2/Bax. Our study identified Arg104, Tyr105, Leu116, and Leu134 to be the common key residues in the Bcl-xL complexes, and Arg107, Tyr108, Phe112, Gln118, Leu137, Arg146, and Tyr202 are common key residues in the Bcl-2 complexes. These results would provide valuable information for the design of potent inhibitors of Bcl-xL/Bcl-2.

Polymer Brush-Grafted Nanoparticles Preferentially Interact with Opsonins and Albumin.

Nanoparticles find increasing applications in life science and biomedicine. The fate of nanoparticles in a biological system is determined by their protein corona, as remodeling of their surface properties through protein adsorption triggers specific recognition such as cell uptake and immune system clearance and nonspecific processes such as aggregation and precipitation. The corona is a result of nanoparticle–protein and protein–protein interactions and is influenced by particle design. The state-of-the-art design of biomedical nanoparticles is the core–shell structure exemplified by superparamagnetic iron oxide nanoparticles (SPIONs) grafted with dense, well-hydrated polymer shells used for biomedical magnetic imaging and therapy. Densely grafted polymer chains form a polymer brush, yielding a highly repulsive barrier to the formation of a protein corona via nonspecific particle–protein interactions. However, recent studies showed that the abundant blood serum protein albumin interacts with dense polymer brush-grafted SPIONs. Herein, we use isothermal titration calorimetry to characterize the nonspecific interactions between human serum albumin, human serum immunoglobulin G, human transferrin, and hen egg lysozyme with monodisperse poly(2-alkyl-2-oxazoline)-grafted SPIONs with different grafting densities and core sizes. These particles show similar protein interactions despite their different “stealth” capabilities in cell culture. The SPIONs resist attractive interactions with lysozymes and transferrins, but they both show a significant exothermic enthalpic and low exothermic entropic interaction with low stoichiometry for albumin and immunoglobulin G. Our results highlight that protein size, flexibility, and charge are important to predict protein corona formation on polymer brush-stabilized nanoparticles.

Equilibrium field theory of magnetic monopoles in degenerate square spin ice: Correlations, entropic interactions, and charge screening regimes

We describe degenerate square spin as an ensemble of magnetic monopoles coupled via an emergent entropic field that subsumes the effect of the underlying spin vacuum. We compute their effective free energy, entropic interaction, correlations, screening, and structure factors that coincide with the experimental ones. Unlike in pyrochlore ices, a dimensional mismatch between real and entropic interactions leads to weak singularities at the pinch points and algebraic correlations at long distance. This algebraic screening can be, however, camouflaged by a pseudo-screening regime.

Rational in silico drug design of HIV-RT inhibitors through G-QSAR and molecular docking study of 4-arylthio and 4-aryloxy-3-iodopyridine-2(1-H)-one derivative

BackgroundHuman immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Antiretroviral therapy (ART) against HIV infection offers the promise of controlling disease progression and prolonging the survival of HIV-infected patients. Reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In this direction, by using group-based QSAR study (G-QSAR), identification of the structural need for the development of lead structure with reverse transcriptase inhibition on 97 reported structures was carried out. Docking analysis was performed further and suggested the structural properties required for binding affinity with the receptor. The molecules in the data set were fragmented into six (R1, R2, R3, R4, R5, and R6) by applying the fragmentation pattern. Three G-QSAR models were selected based on the statistical significance of the model. The molecular docking study was performed to explain the structural properties required for the design of potent HIV-RT inhibitors.ResultsThe statistically validated QSAR models reveal the presence of higher hydrophobic groups containing single-bonded –Br atom, 2 aromatic bonded –NH group with less electronegativity, and entropic interaction fields at R2 essential for better anti-HIV activity. The presence of a lipophilic group at R3, oxygen and sulfur connected with two aromatic bonds at R4, and –CH3 group at R5 was fruitful for reverse transcriptase inhibition. Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond, Van der Waal’s, charge, aromatic, and π–π interactions with residues present at the active site.ConclusionThe results of the generated models provide significant site-specific insight into the structural requirements for reverse transcriptase inhibition during the design and development of novel anti-HIV compounds. Molecular docking study revealed the binding interaction between the ligand and the receptor which gave insight towards the structure-based design for the discovery of more potent compounds with better activity against HIV infection.

Potential of pyrroquinazoline alkaloids from Adhatoda vasica Nees. as inhibitors of 5-LOX – a computational and an in-vitro study

Inflammation plays a major role in the onset and progression of many diseases related to the respiratory system. Cysteinyl leukotrienes, the products of 5-LOX are a potent bronchoconstrictor. Vasicine, vasicinone and deoxyvasicine are the pyrroquinazoline alkaloids of Adhatoda vasica that are well known for their bronchodilatory activity. The current investigation evaluates the 5-LOX inhibitory potential of these alkaloids. Molecular docking results indicated that these alkaloids have similar binding energy as that of Zileuton, a commercial drug. Analysis of the molecular dynamics simulations, the binding free energy derived from MM-PBSA and interaction entropy indicated that vasicinone (-8.33 kcal/mol) exhibited a binding free energy comparable to that of Zileuton (-8.52 kcal/mol). The in-vitro results indicate the potential of vasicinone as a competitive inhibitor, while the in-silico results highlighted the potential of vasicine and deoxyvasicine as allosteric inhibitors. A possible mechanism behind the activity exhibited by the plant was also determined, which emphasized the potential of these alkaloids as leads for the design of novel 5-LOX inhibitors

The concept of spin ice graphs and a field theory for their charges

Originally detected in rare earth pyrochlores, spin ice physics is now being artificially extended to a variety of geometries that control collective behavior and exotic properties, making graph theory their proper framework. We relate spin ice notions, such as ice rule, ice manifold, Coulomb phases, charges, and monopoles, to graph-theoretical notions, such as balance, in/out-degrees, and Euler paths. We then propose a field-theoretical treatment in which topological charges and monopoles are the degrees of freedom, while the binary spins are subsumed in an entropic interaction among charges. We show that for a spin ice on a graph in a Gaussian approximation, the kernel of the entropic interaction is the inverse of the graph Laplacian, and we compute screening functions from the graph spectra as Green operators for the screened Poisson problem on a graph. We then apply the treatment to star graphs, tournaments, cycles, and regular spin ice in different dimensions. Our aim is twofold: to set spin ice physics in a proper graph setting, where only topological rather than geometrical notions hold, and to invite graph theorists to contribute their powerful tools to the field of spin ice.

Quantitative Protein Corona Composition and Dynamics on Carbon Nanotubes in Biological Environments

AbstractWhen nanoparticles enter biological environments, proteins adsorb to form the “protein corona” which alters nanoparticle biodistribution and toxicity. Herein, we measure protein corona formation on DNA‐functionalized single‐walled carbon nanotubes (ssDNA‐SWCNTs), a nanoparticle used widely for sensing and delivery, in blood plasma and cerebrospinal fluid. We characterize corona composition by mass spectrometry, revealing high‐abundance corona proteins involved in lipid binding, complement activation, and coagulation. We investigate roles of electrostatic and entropic interactions driving selective corona formation. Lastly, we study real‐time protein binding on ssDNA‐SWCNTs, obtaining agreement between enriched proteins binding strongly and depleted proteins binding marginally, while highlighting cooperative adsorption mechanisms. Knowledge of protein corona composition, formation mechanisms, and dynamics informs nanoparticle translation from in vitro design to in vivo application.

Quantitative Protein Corona Composition and Dynamics on Carbon Nanotubes in Biological Environments.

When nanoparticles enter biological environments, proteins adsorb to form the "protein corona" which alters nanoparticle biodistribution and toxicity. Herein, we measure protein corona formation on DNA-functionalized single-walled carbon nanotubes (ssDNA-SWCNTs), a nanoparticle used widely for sensing and delivery, in blood plasma and cerebrospinal fluid. We characterize corona composition by mass spectrometry, revealing high-abundance corona proteins involved in lipid binding, complement activation, and coagulation. We investigate roles of electrostatic and entropic interactions driving selective corona formation. Lastly, we study real-time protein binding on ssDNA-SWCNTs, obtaining agreement between enriched proteins binding strongly and depleted proteins binding marginally, while highlighting cooperative adsorption mechanisms. Knowledge of protein corona composition, formation mechanisms, and dynamics informs nanoparticle translation from in vitro design to in vivo application.

Mesoatom alloys via self-sorting approach of giant molecules blends

The bottom-up construction of Frank–Kasper (FK) phases in soft matter requires intricating tuning to balance entropic and enthalpic interactions. In contrast, sophisticated rules have been established in Metallurgy to dictate the packing structures of metal alloys. Inspired by alloy metallurgy, we develop a new self-sorting approach to construct nanostructures in condensed soft matters. This approach utilizes blends of nano-sized giant molecules to construct supramolecular motifs (“mesoatoms”) with controlled size heterogeneity, which is the key in rational design of diverse FK nanostructures. Especially, the scarcely observed thermodynamically stable Laves C14 and C15 phases are widely found. This approach sheds light on next-generation material engineering which allows nanostructure construction in a more predictable and straightforward way

Temperature-Driven Grafted Nanoparticle Penetration into Polymer Melt: Role of Enthalpic and Entropic Interactions

Understanding the fundamentals of nanoparticle (NP) penetration into soft matter systems is indispensable for numerous applications ranging from targeted nanoparticle-based drug delivery to generat...

An Approach to Computing Solvent Reorganization Energy.

A method for accurate calculation of reorganization free energy of an explicit solvent solvating a solute molecule is presented. The method relies on the knowledge of solvation free energy known either from experimental measurement or from accurate calculation. An important part of this approach lies in the calculation of entropy in solute-solvent interaction free energy using the interaction entropy method, combined with the calculation of enthalpy of solvent reorganization based on a finite number of solvent molecules near the solute molecule. This interaction entropy-solvent reorganization or IESR method enables one to compute both enthalpy and entropy components of the solvent reorganization energy from MD simulation of the solvated system. The calculated results are determined by the molecular force field only without any empirical parameter. The current method is applied to computing the reorganization energies of water solvent solvating a wide range of solute molecules including both hydrophilic and hydrophobic ones. The accuracy of the approach is indirectly verified by the excellent agreement of individual enthalpies and entropies of the solvation energies between theory and experiment.

Dominant entropic binding of perfluoroalkyl substances (PFASs) to albumin protein revealed by 19F NMR

Mechanistic insight into protein binding by poly- and perfluoroalkyl substances (PFASs) is critical to understanding how PFASs distribute and accumulate within the body and to developing predictive models within and across classes of PFASs. Fluorine nuclear magnetic resonance spectroscopy (19F NMR) has proven to be a powerful, yet underutilized tool to study PFAS binding; chemical shifts of each fluorine group reflect the local environment along the length of the PFAS molecule. Using bovine serum albumin (BSA), we report dissociation constants, Kd, for four common PFASs well below reported critical micelle concentrations (CMCs) − perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS) − as a function of temperature in phosphate buffered saline. Kd values were determined based on the difluoroethyl group adjacent to the anionic headgroups and the terminal trifluoromethyl groups. Our results indicate that the hydrophobic tails exhibit greater binding affinity relative to the headgroup, and that the binding affinities are generally consistent with previous results showing that greater PFAS hydrophobicity leads to greater protein binding. However, the binding mechanism was dominated by entropic hydrophobic interactions attributed to desolvation of the PFAS tails within the hydrophobic cavities of the protein and on the surface of the protein. In addition, PFNA appears to form hemimicelles on the protein surfaces below reported CMC values. This work provides a renewed approach to utilizing 19F NMR for PFAS-protein binding studies and a new perspective on the role of solvent entropy.

Constituent Isomerism-Induced Quasicrystal and Frank–Kasper σ Superlattices Based on Nanosized Shape Amphiphiles

Naturally, subtle variations in the chemical structures of constituent molecules may significantly affect their multiscale spatial arrangements, properties, and functions. Deceptively simple spheri...

Spectroscopic Investigation of Entropic Canopy-Canopy Interactions of Nanoparticle Organic Hybrid Materials.

Nanoparticle organic hybrid materials (NOHMs) are self-suspended liquid-like nanoparticle-based functional materials consisting of a surface-functionalized inorganic nanocore and oligomeric or polymeric chains. They often exhibit complex intermolecular and intramolecular interactions among their constituents, resulting in versatile physicochemical characteristics that range from glassy solids to solvent-free nanoparticle fluids. A variety of applications involving NOHMs have been investigated thus far, including thermal management fluids, lubricants, magnetic fluids, nanocomposites, electrolytes, water treatment and biomass pretreatment chemicals, and CO2 capture solvents. In particular, NOHMs have recently been recognized as a promising CO2 capture and utilization medium. To capture CO2 more effectively, a variety of specific functional groups of strong chemical affinity to CO2 can be added to the polymeric canopy (enthalpic contribution), and various steric considerations induced by attractive/repulsive interactions among the nanocores and canopies can be introduced (entropic contribution). These occur while maintaining negligible vapor pressure and enhanced thermal stability. Here, we investigated the canopy dynamics of NOHMs with different-sized SiO2 nanocores, aiming to reveal the hidden nature of the entropic interaction occurring in NOHMs. Pulse-field gradient nuclear magnetic resonance spectroscopy (with 1H) was employed to investigate the canopy dynamics of the NOHMs synthesized using 7, 12, and 22 nm SiO2 particles, and these results were compared with those from a ternary mix of all three sizes of SiO2 nanocores. The self-diffusion coefficient and thermal diffusivity were also evaluated.