Energetic Affinity Research Articles

Quantum biochemical analysis of the binding interactions between a potential inhibitory drug and the Ebola viral glycoprotein

Ebola virus disease (EVD) causes outbreaks and epidemics in West Africa that persist until today. The envelope glycoprotein of Ebola virus (GP) consists of two subunits, GP1 and GP2, and plays a key role in anchoring or fusing the virus to the host cell in its active form on the virion surface. Toremifene (TOR) is a ligand that mainly acts as an estrogen receptor antagonist; however, a recent study showed a strong and efficient interaction with GP. In this context, we aimed to evaluate the energetic affinity features involved in the interaction between GP and toremifene by computer simulation techniques using the Molecular Fractionation Method with Conjugate Caps (MFCC) scheme and quantum-mechanical (QM) calculations, as well as missense mutations to assess protein stability. We identified ASP522, GLU100, TYR517, THR519, LEU186, LEU515 as the most attractive residues in the EBOV glycoprotein structure that form the binding pocket. We divided toremifene into three regions and evaluated that region i was more important than region iii and region ii for the formation of the TOR-GP1/GP2 complex, which might control the molecular remodeling process of TOR. The mutations that caused more destabilization were ARG134, LEU515, TYR517 and ARG559, while those that caused stabilization were GLU523 and ASP522. TYR517 is a critical residue for the binding of TOR, and is highly conserved among EBOV species. Our results may help to elucidate the mechanism of drug action on the GP protein of the Ebola virus and subsequently develop new pharmacological approaches against EVD. Communicated by Ramaswamy H. Sarma

Computational Studies Applied to Linalool and Citronellal Derivatives Against Alzheimer's and Parkinson's Disorders: A Review with Experimental Approach.

Alzheimer's and Parkinson's are neurodegenerative disorders that affect a great number of people around the world, seriously compromising the quality of life of individuals, due to motor and cognitive damage. In these diseases, pharmacological treatment is used only to alleviate symptoms. This emphasizes the need to discover alternative molecules for use in prevention. Using Molecular Docking, this review aimed to evaluate the anti-Alzheimer's and anti-Parkinson's activity of linalool and citronellal, as well as their derivatives. Before performing Molecular Docking simulations, the compounds' pharmacokinetic characteristics were evaluated. For Molecular Docking, 7 chemical compounds derived from citronellal, and 10 compounds derived from linalool, and molecular targets involved in Alzheimer's and Parkinson's pathophysiology were selected. According to the Lipinski rules, the compounds under study presented good oral absorption and bioavailability. For toxicity, some tissue irritability was observed. For Parkinson-related targets, the citronellal and linalool derived compounds revealed excellent energetic affinity for α-Synuclein, Adenosine Receptors, Monoamine Oxidase (MAO), and Dopamine D1 receptor proteins. For Alzheimer disease targets, only linalool and its derivatives presented promise against BACE enzyme activity. The compounds studied presented high probability of modulatory activity against the disease targets under study, and are potential candidates for future drugs.

Novel In Silico Insights into Rv1417 and Rv2617c as Potential Protein Targets: The Importance of the Medium on the Structural Interactions with Exported Repetitive Protein (Erp) of Mycobacterium tuberculosis.

Nowadays, tuberculosis is the second leading cause of death from a monopathogenic transmitted disease, only ahead of COVID-19. The role of exported repetitive protein (Erp) in the virulence of Mycobacterium tuberculosis has been extensively demonstrated. In vitro and in vivo assays have identified that Erp interacts with Rv1417 and Rv2617c proteins, forming putative transient molecular complexes prior to localization to the cell envelope. Although new insights into the interactions and functions of Erp have emerged over the years, knowledge about its structure and protein–protein interactions at the atomistic level has not been sufficiently explored. In this work, we have combined several in silico methodologies to gain new insights into the structural relationship between these proteins. Two system conditions were evaluated by MD simulations: Rv1417 and Rv2617c embedded in a lipid membrane and another with a semi-polar solvent to mimic the electrostatic conditions on the membrane surface. The Erp protein was simulated as an unanchored structure. Stabilized structures were docked, and complexes were evaluated to recognize the main residues involved in protein–protein interactions. Our results show the influence of the medium on the structural conformation of proteins. Globular conformations were favored under high polarity conditions and showed a higher energetic affinity in complex formation. Meanwhile, disordered conformations were favored under semi-polar conditions and an increase in the number of contacts between residues was observed. In addition, the electrostatic potential analysis showed remarkable changes in protein interactions due to the polarity of the medium, demonstrating the relevance of Erp protein in heterodimer formation. On the other hand, contact analysis showed that several C-terminal residues of Erp were involved in the protein interactions, which seems to contradict experimental observations; however, these complexes could be transient forms. The findings presented in this work are intended to open new perspectives in the studies of Erp protein molecular interactions and to improve the knowledge about its function and role in the virulence of Mycobacterium tuberculosis.

Bioinformatics Approaches to Predict Mutation Effects in the Binding Site of the Proangiogenic Molecule CD93.

The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multimerin-2 (MMRN2), a pan-endothelial extracellular matrix protein, has been identified as a ligand for CD93, but the interaction mechanism between these two proteins is yet to be studied. In this article, we aim to investigate the structural and functional effects of induced mutations on the binding domain of CD93 to MMRN2. Starting from experimental data, we assessed how specific mutations in the C-type lectin-like domain (CTLD) affect the binding interaction profile. We described a four-step workflow in order to predict the effects of variations on the inter-residue interaction network at the PPI, based on evolutionary information, complex network metrics, and energetic affinity. We showed that the application of computational approaches, combined with experimental data, allowed us to gain more in-depth molecular insights into the CD93-MMRN2 interaction, offering a platform for developing innovative therapeutics able to target these molecules and block their interaction. This comprehensive molecular insight might prove useful in drug design in cancer therapy.

In Silico Analysis of the Antagonist Effect of Enoxaparin on the ApoE4-Amyloid-Beta (Aβ) Complex at Different pH Conditions.

Apolipoprotein E4 (ApoE4) is thought to increase the risk of developing Alzheimer’s disease. Several studies have shown that ApoE4-Amyloid (A) interactions can increment amyloid depositions in the brain and that this can be augmented at low pH values. On the other hand, experimental studies in transgenic mouse models have shown that treatment with enoxaparin significantly reduces cortical A levels, as well as decreases the number of activated astrocytes around A plaques. However, the interactions between enoxaparin and the ApoE4-A proteins have been poorly explored. In this work, we combine molecular dynamics simulations, molecular docking, and binding free energy calculations to elucidate the molecular properties of the ApoE4-A interactions and the competitive binding affinity of the enoxaparin on the ApoE4 binding sites. In addition, we investigated the effect of the environmental pH levels on those interactions. Our results showed that under different pH conditions, the closed form of the ApoE4 protein, in which the C-terminal domain folds into the protein, remains stabilized by a network of hydrogen bonds. This closed conformation allowed the generation of six different ApoE4-A interaction sites, which were energetically favorable. Systems at pH5 and 6 showed the highest energetic affinity. The enoxaparin molecule was found to have a strong energetic affinity for ApoE4-interacting sites and thus can neutralize or disrupt ApoE4-A complex formation.

Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone.

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.

Emergence of Van Hove singularity and topological states in Pb3Bi/Ge(111) Rashba systems

It has been shown recently that the coexistence of Van Hove singularity and geometric phase in ${\mathrm{Pb}}_{3}\mathrm{Bi}\text{/}\mathrm{Ge}(111)$ as a prototypical Rashba system can result in chiral topological superconductivity [W. Qin, L. Li, and Z. Y. Zhang, Nat. Phys. 15, 796 (2019)]. Here, we use first-principles calculations to systematically investigate the structural, electronic, and topological properties of the ${\mathrm{Pb}}_{3}\mathrm{Bi}\text{/}\mathrm{Ge}(111)$ alloyed systems by considering not only the configuration that harbors topological superconductivity considered previously (labeled as the ${\mathrm{T}}_{1}$ phase) but also two other energetically nearly degenerate configurations with high symmetries (labeled as ${\mathrm{H}}_{3}$ and ${\mathrm{T}}_{4}$). We first show that all the three structural configurations have giant Rashba-type spin splittings, resulting from the strong spin-orbit coupling effect of the heavy elements (Pb, Bi) together with inversion symmetry breaking. Next, we demonstrate that each of the saddle- or paraboliclike band dispersions can lead to the emergence of Van Hove singularities, whose positions can be substantially tuned by the giant Rashba effect to the vicinity of the Fermi level. Furthermore, we reveal the existence of topological states in both the ${\mathrm{H}}_{3}$ and ${\mathrm{T}}_{4}$ phases, and the corresponding Rashba-induced band gaps are given by 25 and 50 meV, respectively. Given the energetic affinity of the three phases, these findings suggest the feasibility of realizing quantum phase transitions between quantum spin Hall effect and topological superconductivity within the same materials platform. The present study is expected to give new insights in searching for topological quantum states including 2D topological superconductivity based on Rashba systems.

Ivabradine possesses anticonvulsant and neuroprotective action in mice

We analyzed whether ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, clinically used for angina and arrhythmia, had anticonvulsant, antioxidant and neuroprotective properties against classical seizure models. Potential molecular targets to IVA anticonvulsant effects were evaluated by molecular docking. Mice were treated with IVA (1, 10 or 20 mg/kg, IP) for 3 days, and 30 min after the last administration were injected with pentylenetetrazole (PTZ - 85 mg/kg, IP), pilocarpine (PILO 400 mg/kg, SC), picrotoxin (PICRO 10 mg/kg, IP). The following measures were performed: presence of seizures, latency for the first seizure, latency for death, percentage of survival. Antioxidant activity was investigated by determination of lipid peroxidation (MDA), reduced glutathione (GSH) and nitrite levels in the prefrontal cortex (PFC), hippocampus and striatum (ST). Immunohistochemistry analysis for cleaved caspase-3, a pro-apoptotic and degenerative marker, in hippocampal subregions namely cornu ammonis (CA)1, CA3 and dentate gyrus (DG), were also performed. IVA attenuated PTZ- and PICRO-induced seizures while presented an antioxidant effect in all brain areas studied. IVA markedly reduced cleaved caspase-3 expression in the CA1 and DG region of PICRO- and PTZ-treated mice, respectively. Molecular docking demonstrated that IVA has high energetic affinity and binding compatibility for GABAA receptor without causing channel obstruction. However, no reproducibility in the binding of IVA to N-methyl-d-aspartate (NMDA) receptor was detected. In conclusion, IVA has anticonvulsant, antioxidant and neuroprotective effects against PTZ- and PICRO-induced seizures. Also, a high affinity of IVA to GABAA receptor was predicted, representing a potential underlying mechanism to these observable effects.

Merger of Energetic Affinity and Optimal Geometry Provides New Class of Boron Nitride Based Sorbents with Unprecedented Hydrogen Storage Capacity.

Hydrogen is an ideal synthetic fuel because it is lightweight, abundant and its oxidation product (water) is environmentally benign. However, its utilization is impeded by the lack of an efficient storage device. A new building block approach is proposed for an exhaustive search of optimal hydrogen uptakes in a series of low density boron nitride (BN) nanoarchitectures via extensive 3868 ab initio-based multiscale simulations. By probing various geometries, temperatures, pressures, and doping ratios, these results demonstrate a maximum uptake of 8.65 wt% at 300 K, the highest hydrogen uptake on sorbents at room temperature without doping. Li+ doping of the nanoarchitectures offers a set of optimal combinations of gravimetric and volumetric uptakes, surpassing the US Department of Energy targets. These findings suggest that the merger of energetic affinity and optimal geometry in BN building blocks overcomes the intrinsic limitations of sorbent materials, putting hybrid BN nanoarchitectures on equal footing with hydrides while demonstrating a superior capacity-kinetics-thermodynamics relationship.

Oxygen intercalation in Ruddlesden-Popper type Sr3LaFe3O10-δ

The oxygen nonstoichiometry of Ruddlesden-Popper type Sr3LaFe3O10-δ, a promising parent material for mixed-conducting electrodes and membranes, was studied in the oxygen partial pressure range from 10−24 to 0.5 atm at 973–1223 K by coulometric titration and thermogravimetry. The p(O2)-T-δ diagram can be described using a statistical thermodynamic model relating the non-ideal behavior in oxidizing and strongly reducing atmospheres to the coulombic interaction between oxygen vacancies and electronic charge carriers. The results confirm a strong energetic affinity of anion vacancies to the central perovskite-like layers of the Ruddlesden-Popper structure, whilst the difference between crystallographic iron sites has no significant effects on the oxygen intercalation thermodynamics at elevated temperatures. No indications of long-range ordering in the oxygen sublattice were observed.

Defect Interactions in Sr3La(Fe,Al)3O10−δ by Computer Simulations and Mössbauer Spectroscopy

Moderate Al3+ doping in Ruddlesden−Popper type Sr3LaFe3O10−δ leads to complete reconfiguration of the electronic sublattice. While oxygen vacancies, Fe4+, and substitutional cations all exhibit energetic affinity for the equatorial perovskite-like planes, the atomistic computer simulations showed that Coulombic repulsion between the point defects and local lattice deformations near Al3+ result in hole displacement out of these layers when the content of vacant anion sites and/or aluminum is significant. The Al3+ cations tend to form relatively stable aluminum−oxygen tetrahedra, which are energetically favorable for the central perovskite layers and distort neighboring polyhedra formed by iron. These effects and partial hole localization in the apical iron−oxygen polyhedra adjacent to Al3+ were confirmed by Mössbauer spectroscopy analysis of Sr3LaFe3−xAlxO10−δ (x = 0.3−0.6, δ = 0−1).

A model for the viscoelastic behavior of nanofilled hydrogel composites under oscillatory shear loading

AbstractA molecular model is proposed to predict the viscoelastic response of the hydrogels reinforced with nonpercolated nanoparticles with emphasis on the role of polymer–particle energetic interactions. The structure of the polymer layer adsorbed on the surface of the particles is analyzed using a scaling theory for reversible polymer adsorption. The energetic affinity between the monomers and filler surface is assumed to be weak and short range. Because of thermal fluctuations or the applied deformation, the transient junctions between the polymer segments and filler particles break after a finite period of time. The dynamics of the polymer segments is studied by a Maxwell type kinetic model. The resultsshow that monomer–filler energetic affinity can strongly affect the overall viscoelastic response of the hydrogel nanocomposite, even within the range of weak coupling between the monomers and filler surface. The model can also predict the strain amplitude dependence of the storage shear modulus based on the kinetics of adsoption/desorption of the interfacial monomers. The model predictions are compared with the experimental results for poly(L‐lactide‐co‐ethylene oxide‐co‐fumarate) hydrogels reinforced with hydroxyapatite nanoparticles. The filled hydogel/apatite nanocomposites are useful as a model matrix to mimic the soft elastic and hard mineral phases of the bone matrix and as scaffolds for hard tissue regeneration. POLYM. COMPOS., 2008. © 2008 Society of Plastics Engineers

Oxygen ionic conductivity, Mössbauer spectra and thermal expansion of CaFe 2O 4 - δ

Thermogravimetric analysis showed a very low level of oxygen deficiency ( δ) in CaFe 2O 4 − δ , varying in the range 0.003–0.006 at oxygen partial pressures from 10 − 5 to 0.21 atm and 295–1223 K, in agreement with Mössbauer spectroscopy. This results in substantial dimensional stability on reducing p(O 2) as revealed by the controlled-atmosphere dilatometry, but also in low concentrations of the ionic and electronic charge carriers. The steady-state oxygen permeability of dense CaFe 2O 4 − δ ceramics is determined by both bulk ionic conduction and surface exchange kinetics. The oxygen-ion transference numbers calculated from the faradaic efficiency and permeation data, are (0.2–7.2) × 10 − 4 at 1123–1273 K, increasing with temperature. The atomistic computer simulations indicate a significant energetic affinity for the defect cluster formation involving oxygen vacancies and Fe 2+ cations, and unfavorable vacancy location in the oxygen sites forming one-dimensional pathways with minimum migration energy. As a consequence, the partial oxygen-ionic conductivity of CaFe 2O 4 − δ is as low as 3–210 μS/cm at 1123–1273 K in air. The average thermal expansion coefficients of calcium ferrite ceramics lie in the range (12.0–13.9) × 10 − 6 K − 1 .

Modeling the Viscoelastic Response of Suspension of Particles in Polymer Solution: The Effect of Polymer‐Particle Interactions

AbstractA conceptual model is proposed for the viscoelastic response of dilute polymer solutions containing well‐dispersed low volume fraction spherical particles. The equilibrium structure of the reversibly adsorbed polymer layer on the particle surface was characterized by a scaling theory. The dynamics of the polymer chains were studied by a Maxwell type kinetic model. At the limit of small particle size, our results show that the monomer‐filler energetic affinity, particle volume fraction and surface friction strongly affect the overall viscoelastic response of the filled solutions and lead to unusual viscoelastic properties that have been observed experimentally. These properties include a dramatic increase in shear viscosity, intense shear thinning, and solid‐like behavior at low frequency domains.magnified image

The Role of Polymer-particle Interactions on the Viscoelastic Properties of Polymer Nanocomposites

ABSTRACTA molecular model is proposed for the dynamics of polymer chains in dilute polymer solutions containing well-dispersed spherical particles. In the presence of short range energetic affinity between the monomers and filler surface, the equilibrium structure of the adsorbed polymer layer is determined by a scaling theory. The viscoelastic response of the suspension is studied by a Maxwell model. It is shown that the solid-like properties of polymer nanocomposites in low frequency regimes could be attributed to the slowdown of the relaxation process of polymer chains. This process is controlled by the monomer-particle frictional interactions, density of the adsorbed polymer chains on the particles surface (controlled by monomer-particle adsorption energy), and volume fraction of the interfacial layer which can be enhanced by reduction of filler size or increasing the filler concentration.

Energetically driven liquid–solid transitions in molecularly thin n-octane films

In this paper we present findings from molecular dynamics simulations that investigated the changes induced in molecularly thin n-octane films, as a result of increasing solid-methylene unit energetic affinity. The solid surfaces were deprived of any topographical features and were modeled as atomically smooth 10-4 Lennard–Jones planes. We observed an abrupt transition in the structural features of the film at a critical value of the characteristic energy that quantified the affinity between solid surfaces and methylene units. The transition was signaled by a discontinuous increase in the degree of intermolecular order and facilitated by a precipitous extension of the octane molecules, which adopted almost fully extended configurations. Furthermore, the transition resulted in the freezing of molecular migration and rotation. The characteristics of the transition showed that it is a mild first order phase transition between a highly ordered liquid and a poorly organized solid. The solid constitutes a phase with order intermediate to that of hydrocarbon ‘‘rotator’’ phases and two-dimensional smectics. These findings demonstrate that solidification of nanoscopically thin films of linear alkanes is a general, energetically driven phenomenon, which does not require the aid of commensurate surface topography. Our simulations provide a natural explanation for the solidlike features exhibited by alkane films studied experimentally.

Structural transitions at solid-liquid interfaces

In this paper we present the findings of our investigations using molecular dynamics, on molecularly thin films of n-octane confined between topographically smooth solid surfaces. We focus on the effect of increasing solid surface-methylene unit energetic affinity and the effect of increasing pressure (normal load) of the film in inducing liquid-solid phase transitions. We observed an abrupt transition in the structural features of the film at a critical value of the characteristic energy that quantified the affinity between solid surfaces and methylene units. This energetically driven transition was evident from the discontinuous increase of intermolecular order, a precipitous extension of the octane molecules and freezing of molecular migration and rotation. Increasing pressure had a similar effect in inducing a liquid-solid phase transition. The characteristics of the transition showed that it is a mild first order transition from a highly ordered liquid to a poorly organized solid. These findings demonstrate that the solidification of nanoscopically thin films of linear alkanes is a general phenomenon (driven either energetically or by increasing pressure), and does not require the aid of commensurate surface topography.

Energetically and pressure driven phase transitions in molecularly thin films of n-alkanes

Molecular dynamics simulations were carried out on molecularly thin films of n-octane confined between topographically smooth solid surfaces. We focused on determining the effect of increasing solid surface-methylene unit energetic affinity and the effect of increasing pressure (normal load) of the film in inducing liquid-solid phase transitions. Simulations of films wide enough to accomodate three segmental layers showed an abrupt transition in the structural features at a critical value of the characteristic energy that quantified the affinity between solid surfaces and methylene units. This energetically driven transition was evident from the discontinuous increase of intermolecular order, a precipitous extension of the octane molecules and freezing of molecular migration and rotation. Increasing pressure had a similar effect in inducing a liquid-solid phase transition. The characteristics of the transition showed that it is a mild first-order transition from a highly ordered liquid to a poorly organized solid. These findings demonstrate that the solidification of nanoscopically thin films of linear alkanes is a general phenomenon (driven either energetically or by increasing pressure), and does not require the aid of commensurate surface topography. Our findings on relatively wider films (5 segmental diameters wide) show that the interfacial layer undergoes a similar first-order phase transition with increasing solid-methylene unit energetic affinity. This energy threshold is significantly higher than the one observed in thin film simulations.

Energetically and Pressure Driven Liquid-Solid Transitions in Molecularly Thin Hydrocarbon Films

ABSTRACTIn this study we used molecular dynamics simulations to investigate the structural changes in nanoscopically thin n-octane films confined between smooth solid surfaces as a result of a) increasing solid-methylene unit affinity and b) increasing pressure. Increasing solid-methylene unit energetic affinity resulted in the solidification of the film at a critical value. A similar transition is observed at a critical value of pressure. Bulk n-octane was a liquid in both cases. The transition was signaled by an abrupt increase in the intermolecular order and was facilitated by a precipitous extension of the octane molecules, which adopted almost fully extended configurations. A discontinuous jump in the film density at the critical values of solid affinity and pressure was evident. The characteristics of the transitions showed that it was a mild first order transition from a highly ordered liquid to a poorly organized solid.

The enthalpy of dilution of o-terphenyl in benzene and the temperature dependence of interaction parameters

Enthalpies of dilution of o-terphenyl in benzene were measured calorimetrically at 288.15, 293.15, 298.15, 303.15, and 308.15 K. In the range of the volume fraction near the solubilities to high dilutions, φ 2 ≈ 0.7 to 0.04, enthalpies of dilution observed are all positive. The enthalpy parameter χ H and its dependence on volume fraction calculated from experimental results are reproduced by the linear functions: 0.091 1−0.01 0 φ 2 , 0.079 9+0.007 4 φ 2 , 0.068 5+0.003 6 φ 2 , 0.062 4 + 0.005 4, φ 2 , and 0.056 8−0.002 2 φ 2 , respectively at 288.15, 293.15, 298.15, 303.15, and 308.15 K, where φ 2 is a volume fraction of o-terphenyl. These observations show that χ H decreases with rise of temperature. A comparison of χ H among the isomers at 298.15 K show that the relative order of energetic affinity for benzene in solution is ortho- > meta- > para-terphenyls.