Search Results (363)

This study presents a systematic investigation of the dynamic and structural characteristics of St. John’s wort (Hypericum perforatum) in alcoholic solutions using experimental and theoretical techniques. Ultrasonic relaxation spectroscopy was employed to investigate medium-range dynamic processes, while density functional theory (DFT) calculations were employed to explore the molecular structure and vibrational properties of the system. Theoretical calculations revealed two Hyperforin conformers, a keto derivative, and three protonated species. Acoustic spectra revealed three distinct Debye-type relaxation processes, corresponding to conformational changes in hyperforin, enol-to-keto tautomerization, and proton transfer mechanisms. In addition, St. John’s wort oil (Oleum Hyperici) was studied, using attenuated total reflection (ATR) infrared spectroscopy for several extraction intervals. These spectra were compared with the theoretical IR spectra of hypericin, hyperforin, and its derivatives, confirming the presence of hyperforin, keto, and two protonated species in the oil. Besides structural and dynamical evaluations, the study assessed the toxicity and biological activity of hyperforin and all species found in the solutions, offering information about potential pharmaceutical uses, suggesting that hyperforin and its keto form have the best antidepressant activity. This comprehensive analysis enhances the understanding of hyperforin’s molecular behavior and strengthens the therapeutic potential of St. John’s wort as a natural antidepressant agent. Full article

Helicobacter pylori urease (HpU) plays a central role in bacterial survival and virulence by hydrolyzing urea into ammonia and carbon dioxide, neutralizing gastric acidity, and facilitating host colonization. The increasing prevalence of antibiotic resistance underscores the need for alternative strategies targeting essential bacterial enzymes such as urease. In this study, a multistage computational pipeline integrating pharmacophore modeling, machine learning (ML), ensemble docking, and enhanced molecular dynamics simulations were applied to identify novel triazole-based HpU inhibitors. Starting from over seven million compounds in the ZINC15 database, pharmacophore- and ML-based filters progressively reduced the chemical space to 7062 candidates. Ensemble docking across 25 conformational frames of HpU, followed by quantum-polarized ligand docking (QPLD), identified seven promising ligands exhibiting strong binding energies and stable metal coordination. Molecular dynamics (MD) simulations under progressively relaxed restraints revealed three highly stable complexes (CA1, CA3, and CA6). Subsequent well-tempered metadynamics (WT-MetaD) simulations reconstructed free-energy landscapes showing deep, localized basins for CA3 and CA6, comparable to the potent reference inhibitor DJM, supporting their potential as strong urease binders. Finally, unsupervised chemical space mapping using the UMAP algorithm positioned these candidates within molecular regions associated with potent urease inhibitors, further validating their structural coherence and pharmacophoric relevance. An ADMET assessment confirmed that the selected candidates exhibit physicochemical and early safety properties compatible with subsequent in vitro evaluation. This multilevel screening strategy demonstrates the power of combining ML-driven classification, ensemble docking, and enhanced sampling simulations to discover non-hydroxamic urease inhibitors. Although the current findings are computational, they provide a rational foundation for future in vitro validation and for expanding the discovery of triazole-based scaffolds targeting ureolytic enzymes. Full article

The mechanical behavior of nanoparticle assemblies depends strongly on particle size, yet the underlying mechanisms remain insufficiently understood. In present study, we employ a scheme combining discrete element method (DEM) and molecular dynamics (MD) simulations to examine size-dependent strength and deformation in disordered copper nanoparticle assemblies. Granular packings generated by DEM were transformed into atomic models and subjected to uniaxial compression in MD simulations. Assemblies composed of nanoparticles with radius smaller than ~2.5 nm fully densify during relaxation, forming nanopolycrystalline solids, whereas larger particles preserve porous architectures. This structural divergence governs subsequent deformation. Small-particle assemblies deform through grain boundary migration and grain growth, exhibiting an inverse Hall–Petch-type strength dependence. In contrast, large-particle assemblies deform primarily via interparticle contact evolution and densification, with strength conforming to a Gibson–Ashby-type prediction. A scaling law captures the strength variation across size range in this regime. These results establish the competition between surface energy-driven densification and contact-dominated deformation as the controlling factor in the mechanical response of nanoparticle assemblies, providing guidance for designing nanoparticle-based materials with tailored mechanical performance. Full article

Triarylmethyl radicals (TAMs) have recently emerged as highly effective polarizing agents in dynamic nuclear polarization (DNP) under viscous conditions, enabling substantial hyperpolarization via the solid-effect (SE) DNP mechanism even at room temperature. A comparable, though less pronounced, enhancement was observed for BDPA radicals embedded in phosphocholine-based lipid bilayers. Given the increasing interest in elucidating the structure and dynamics of biopolymers and their high-molecular-weight assemblies—such as cell membranes—this study focuses on the design, synthesis, and characterization of paramagnetic agents tailored for DNP-based structural biology. To this end, we synthesized a series of TAM derivatives functionalized with lipophilic substituents and characterized their magnetic resonance properties, including isotropic hyperfine interaction (HFI) constants on carbon nuclei and electron spin relaxation times (T₁ and T_m) at low temperatures (80 K). Echo-detected EPR spectra and electron spin echo envelope modulations (ESEEM) were recorded for novel TAM incorporated into liposomes composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). These low-temperature measurements revealed that the radicals are localized either at the liposome surface or within the lipid bilayer, ensuring optimal accessibility to water molecules. Crucially, the presence of a single cholesterol moiety provides strong noncovalent anchoring within the hydrophobic core of the bilayer. Guided by these findings, we identify an amphiphilic TAM bearing a single cholesterol group and polar carboxyl functionalities as a highly promising candidate for DNP applications in membrane biology, combining efficient polarization transfer, bilayer integration, and aqueous accessibility. Full article

Deep Eutectic Solvents (DESs) have emerged as promising candidates to replace conventional organic solvents in various technological applications due to their low vapor pressure, non-flammability, and ease of preparation at low costs. In particular, Type IV DESs, which are composed of metal salts and hydrogen bond donors, are possible replacements for lithium-ion battery electrolytes. In this study, we investigate the molecular dynamics of solvents of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) and pyrazole (PYR) at varying LiTFSI:PYR molar ratios (1:2, 1:3, 1:4, 1:5) using Nuclear Magnetic Resonance Dispersion (NMRD) and Pulsed Field Gradient (PFG) Nuclear Magnetic Resonance (NMR). PFG NMR reveals composition-dependent diffusion trends, while NMRD provides molecular-level insights into the longitudinal relaxation rate (R₁ = 1/T₁). Notably, the LiTFSI:PYR (1:2) sample shows distinct behavior across both techniques, exhibiting enhanced relaxation rates and lower self-diffusion for ¹H compared to the other nuclei (¹⁹F and ⁷Li), suggestive of stronger and more efficient Li⁺–pyrazole interactions, as confirmed by the modeling of the relaxation profiles. Our study advances understanding of ion dynamics in azole-based eutectic solvents, supporting their potential use in safer battery electrolytes. Full article

Homeostasis, which supports and maintains brain function, results from the continuous regulation of thermodynamics within tissue: the balance of heat production, redox oscillations, and vascular convection regulates coherent energy flow within the organ. Neuroinflammation disturbs this balance, creating measurable entropy gradients that precede structural damage to its tissue components. This paper proposes that a thermodynamic unity can be devised that incorporates nanoscale physics, energetic neurophysiology, and systems neuroscience, and can be used to understand and treat neuroinflammatory processes. Using multifactorial modalities such as quantum thermometry, nanoscale calorimetry, and redox oscillometry we define how local entropy production (s_t), relaxation time (τ^R), and coherence lengths (λc) allow quantification of the progressive loss of energetic symmetry within neural tissues. It is these variables that provide the basis for the etiology of thermodynamic biomarkers which on a molecular-redox-to-network scale characterize the transitions governing the onset of the neuroinflammatory process as well as the recovery potential of the organism. The entropic probing of systems (PEP) further allows the translation of these parameters into dynamic patient-specific trajectories that model the behavior of individuals by predicting recurrent bouts of instability through the application of machine learning algorithms to the vectors of entropy flux. The parallel development of the nanothermodynamic intervention, which includes thermoplasmonic heat rebalancing, catalytic redox nanoreacting systems, and adaptive field-oscillation synchronicity, shows by example how the corrections that can be applied to the entropy balance of the cell and system as a whole offer a feasible form of restoration of energy coherence. Such closed loop therapy would not function by the suppression of inflammatory signaling, but rather by the re-establishment of reversible energy relations between mitochondrial, glial, and vascular territories. The combination of these factors allows for correction of neuroinflammation, which can now be viewed from a fresh perspective as a dynamic phase disorder that is diagnosable, predictable, and curable through the physics of coherence rather than the molecular suppression of inflammatory signaling. The significance of this set of ideas is considerable as it introduces a feasible and verifiable structure to what must ultimately become the basis of a new branch of science: predictive energetic medicine. It is anticipated that entropy, as a measurable and modifiable variable in therapeutic “inscription”, will be found to be one of the most significant parameters determining the neurorestoration potential in future medical science. Full article

The operational stability of organic solar cells critically depends on the excited-state characteristics of electron acceptor materials. Through systematic quantum chemical calculations on four representative acceptors (PCBM, ITIC, Y6, and TBT-26), this study reveals fundamental spectra–stability relationships. Non-fullerene acceptors demonstrate superior light-harvesting with systematically tuned energy levels and significantly lower exciton binding energies (2.05–2.12 eV) compared to PCBM (2.97 eV), facilitating efficient charge separation. Structural dynamics analysis uncovers distinct stability mechanisms: ITIC maintains exceptional structural integrity (anionic RMSD = 0.023, S₁ RMSD = 0.134) with superior bond preservation, ensuring balanced performance–stability. Y6 exhibits substantial structural relaxation in excited states (S₁ RMSD = 0.307, T₁ RMSD = 0.262) despite its low exciton binding energy, indicating significant non-radiative losses. TBT-26 employs selective bond stabilization, preserving acceptor–proximal bonding despite considerable anionic flexibility. These findings establish that optimal molecular design requires both favorable electronic properties and structural preservation in photoactive states, providing crucial guidance for developing efficient and stable organic photovoltaics. Full article

Magnetic Resonance Relaxometry is a powerful technique that reveals a sample’s molecular dynamics thanks to the dependence of the T₁ relaxation time on field strength. With applications in protein research, food systems, material development, and environmental science, relaxometry measurements are typically undertaken using a technique known as fast field cycling, where T₁ is measured at a range of detection fields. However, the sample experiences relaxation in a variable field without the challenges associated with retuning a probe to each of the necessary frequencies of interest. This technique is limited by a maximum relaxation time, since the measurement and relaxation fields are typically applied using a fluid-cooled electromagnet, which will ultimately overheat for very long experimental times. In this work, we propose an alternative approach to permit measurements of samples with inherently long T₁ values. We utilise a broadband spectrometer alongside a solenoid transmit-receive coil and custom tuning and matching boards, whilst two sets of magnets are moved around the coil, to achieve a range of different fields. By collecting a reduced number of points and utilising this method, we show it is still possible to make useful measurements on samples at a range of frequencies, which has great potential in quality assurance applications. We find a similar trend for food samples of corn oil, while manganese chloride, a common contrast agent, has more than a 100% difference when compared to traditional fast field cycling measurements. Full article

The slow swelling rate of styrene–butadiene–styrene (SBS) in asphalt prolongs the modification process and increases energy consumption. This study proposes a novel method using benzoyl peroxide (BPO) and benzoyl methane (BPA) to accelerate SBS swelling through a radical initiation–capture mechanism. BPO generates free radicals that relax the SBS network, while BPA captures excess radicals, maintaining system stability. Molecular dynamics simulations based on the COMPASS II force field were used to analyse diffusion, radius of gyration, and solubility parameters, revealing that BPO/BPA improved SBS–asphalt compatibility and increased the diffusion coefficient by 76%. Macroscopic viscosity tests confirmed that the swelling time decreased by 40% and equilibrium viscosity increased by 39% compared with the conventional process. The modified asphalt also exhibited enhanced high- and low-temperature performance and ageing resistance. This simple and efficient synergistic technique provides a promising approach for the rapid preparation of SBS-modified asphalt and offers practical potential for industrial production. Full article

Protein–protein docking is a cornerstone of computational structural biology, yet its reliability for large, multimeric assemblies remains uncertain. Standard workflows typically include geometry optimization or molecular dynamics equilibration to relieve local strains and improve input quality, but the extent to which these preparatory steps alter docking outcomes has not been systematically evaluated. Here, we address this question using the mitochondrial chaperonin Hsp60, a dynamic double-ring complex essential for protein folding, and MIX, a kinetoplastid-specific protein with unresolved function, as a stress test system. By comparing docking predictions across minimized, equilibrated, and ensemble-refined structures of Hsp60 in three conformational states (apo, ATP-bound, and ATP–Hsp10), we show that structural relaxation profoundly reshapes the docking landscape. Minimization alone often yielded favorable scores but localized binding, while longer MD trajectories exposed alternative sites, including central cavity, equatorial ATP pocket, and apical domain, each consistent with distinct regulatory hypotheses. These findings reveal that docking outcomes are highly sensitive to receptor preparation, especially in complexes undergoing large conformational transitions. More broadly, our study highlights an underappreciated vulnerability of docking pipelines and calls for ensemble-based and dynamics-aware approaches when predicting interactions in large biomolecular machines. Full article

Chitosan films obtained by solution casting were investigated by broadband dielectric spectroscopy (BDS) to explore both their glass transition and the effects of thermal annealing on molecular dynamics, deriving from residual water content as well as from cold crystallization. Glass transition at low temperatures could be evidenced in as-produced as well as thermally annealed films, where non-Arrhenian dielectric relaxation processes, consistent with a structural (α) relaxation, could be detected. The process detected at low temperatures could reflect the dynamics of residual water slaved by the polymer matrix. Secondary (β) relaxations, along with a slow process ascribed to interfacial polarization at the amorphous/crystalline interfaces, were concurrently detected. In most cases, a further Arrhenian process at intermediate temperatures (α_c) was present, also indicative of crystallization. Notably, the α processes, due to the primary relaxation of the polymer matrix plasticized by water, could be discriminated from other processes, present in the same frequency range, thanks to improvements in the dielectric fitting strategy. All relaxation processes showed the expected dependence on T_a. The more accurate exploration of the glass transition for chitosan helps to better rationalize its crystallization behavior, in view of an optimized application of this biopolymer. Full article

This work investigates the influence of chemical composition, grain boundary (GB) type, and atomic distribution on the thermal conductivity of Hf–Nb–Ta–Zr refractory high-entropy alloys (RHEAs) via atomistic simulations. Three compositions—equiatomic HfNbTaZr (M1), Hf₁₀Nb₄₀Ta₁₀Zr₄₀ (M2), and Hf₄₀Nb₁₀Ta₄₀Zr₁₀ (M3)—were studied in single-crystalline and bicrystalline models containing Σ3 or Σ5 GBs. The effect of chemical short-range order (SRO) and GB segregation was probed by comparing results for non-relaxed structures with those obtained for corresponding materials relaxed using combined Monte Carlo/molecular dynamics (MC/MD) simulation. Material relaxation is accompanied by the formation of coherent nanoclusters (NbTa in M1, Nb or Zr in M2, Hf or Ta in M3) and Hf/Zr segregation to GBs. In single crystals, SRO reduces thermal conductivity by up to ~2.7% (e.g., from 3.66 to 3.56 W/m·K in M1), which is explained by the phonon scattering effect from matrix–cluster interfaces, densely distributed in the structures. In contrast, in certain bicrystals, the combined effects of GB healing and intragranular cluster coarsening lead to a 6.9% increase in thermal conductivity (from 4.59 to 4.93 W/m·K), despite the presence of high-energy Σ5 GBs. These results demonstrate that the interplay between SRO, GB segregation, and microstructural evolution governs phonon transport in RHEAs, revealing a counterintuitive pathway to enhance thermal conductivity through controlled atomic redistribution. Full article

Proton spin–lattice and spin–spin NMR relaxation studies were conducted on lung tissue samples from 10 patients. For each case, relaxation properties of tumor tissue were compared with those of the corresponding reference tissue. The spin–lattice relaxation measurements were performed over a wide frequency range, from 10 kHz to 10 MHz, spanning three orders of magnitude. These were complemented by both spin–lattice and spin–spin relaxation data acquired at 18.7 MHz. Notably, the spin–spin relaxation process exhibited a bi-exponential character. This relaxation behavior was quantitatively analyzed using dedicated models to achieve two main goals: to evaluate the diagnostic potential of low-field NMR relaxometry, and to gain insights into the dynamics of water and macromolecules in tissue, in comparison with aqueous solutions of proteins and polymers. The frequency dependence of the spin–lattice relaxation rates was well described by a power-law function, with an exponent of approximately 0.3 closely matching the theoretical prediction for reptation dynamics in polymer systems, associated with the intermolecular relaxation contribution. The combined analysis of spin–lattice and spin–spin relaxation data revealed specific parameters (such as ratios between the relaxation rates or between the amplitudes of individual relaxation components) that can be considered as potential markers of pathological changes affecting molecular dynamics in tissues. Full article

Prostate stem cell antigen (PSCA) is a Ly6/uPAR protein that targets neuronal nicotinic acetylcholine receptors (nAChRs). It exists in membrane-tethered and soluble forms, with the latter upregulated in Alzheimer’s disease. We hypothesize that PSCA may be linked to a wider spectrum of neurological diseases and could induce neuroinflammation. Indeed, PSCA expression is significantly upregulated in the brain of patients with multiple sclerosis, Huntington’s disease, Down syndrome, bipolar disorder, and HIV-associated dementia. To investigate PSCA’s structure, pharmacology, and inflammatory function, we produced a correctly folded water-soluble recombinant analog (ws-PSCA). In primary hippocampal neurons and astrocytes, ws-PSCA differently regulates secretion of inflammatory factors and adhesion molecules and induces pro-inflammatory responses by increasing TNFβ secretion. Heteronuclear NMR and ¹⁵N relaxation measurements reveal a classical β-structural three-finger fold with conformationally disordered loops II and III. Positive charge clustering on the molecular surface suggests the functional importance of ionic interactions by these loops. Electrophysiological studies in Xenopus oocytes point on ws-PSCA inhibition of α3β2-, high-, and low-sensitive variants of α4β2- (IC₅₀ ~50, 27, and 15 μM, respectively) but not α4β4-nAChRs, suggesting targeting of the β2 subunit. Ensemble docking and molecular dynamics simulations predict PSCA binding to high-sensitive α4β2-nAChR at α4/β2 and β2/β2 interfaces. Complexes are stabilized by ionic and hydrogen bonds between PSCA’s loops II and III and the primary and complementary receptor subunits, including glycosyl groups. This study gives new structural and functional insights into PSCA’s interaction with molecular targets and provides clues to understand its role in the brain function and mental disorders. Full article

Conformational heterogeneity is essential for protein function, yet validating theoretical molecular dynamics (MD) ensembles remains a significant challenge. In this study, we present an approach that integrates free MD simulations, starting from an AlphaFold-generated structure, with refined experimental NMR-relaxation data to identify biologically relevant holistic time-resolved 4D conformational ensembles. Specifically, we select trajectory segments (RMSD plateaus) consistent with experimental observables. For the extracellular region of Streptococcus pneumoniae PsrSp, we found that only specific segments of the long MD trajectory aligned well with experimental data. The resulting ensembles revealed two regions with increased flexibility, both of which play important functional roles. Full article