Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding.

TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. The isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy.

An electric molecular motor.

Macroscopic electric motors continue to have a large impact on almost every aspect of modern society. Consequently, the effort towards developing molecular motors1-3 that can be driven by electricity could not be more timely. Here we describe an electric molecular motor based on a [3]catenane4,5, in which two cyclobis(paraquat-p-phenylene)6 (CBPQT4+) rings are powered by electricity in solution to circumrotate unidirectionally around a 50-membered loop. The constitution of the loop ensures that both rings undergo highly (85%) unidirectional movement under the guidance of a flashing energy ratchet7,8, whereas the interactions between the two rings give rise to a two-dimensional potential energy surface (PES) similar to that shown by FOF1 ATP synthase9. The unidirectionality is powered by an oscillating10 voltage11,12 or external modulation of the redox potential13. Initially, we focused our attention on the homologous [2]catenane, only to find that the kinetic asymmetry was insufficient to support unidirectional movement of the sole ring. Accordingly, we incorporated a second CBPQT4+ ring to provide further symmetry breaking by interactions between the two mobile rings. This demonstration of electrically driven continual circumrotatory motion of two rings around a loop in a [3]catenane is free from the production of waste products and represents an important step towards surface-bound14 electric molecular motors.

Electron-catalysed molecular recognition.

Molecular recognition1-4 and supramolecular assembly5-8 cover a broad spectrum9-11 of non-covalently orchestrated phenomena between molecules. Catalysis12 of such processes, however, unlike that for the formation of covalent bonds, is limited to approaches13-16 that rely on sophisticated catalyst design. Here we establish a simple and versatile strategy to facilitate molecular recognition by extending electron catalysis17, which is widely applied18-21 in synthetic covalent chemistry, into the realm of supramolecular non-covalent chemistry. As a proof of principle, we show that the formation of a trisradical complex22 between a macrocyclic host and a dumbbell-shaped guest-a molecular recognition process that is kinetically forbidden under ambient conditions-can be accelerated substantially on the addition of catalytic amounts of a chemical electron source. It is, therefore, electrochemically possible to control23 the molecular recognition temporally and produce a nearly arbitrary molar ratio between the substrates and complexes ranging between zero and the equilibrium value. Such kinetically stable supramolecular systems24 are difficult to obtain precisely by other means. The use of the electron as a catalyst in molecular recognition will inspire chemists and biologists to explore strategies that can be used to fine-tune non-covalent events, control assembly at different length scales25-27 and ultimately create new forms of complex matter28-30.

Copper(II) coordination to the intrinsically disordered region of SARS-CoV-2 Nsp1.

The intrinsically disordered C-terminal peptide region of severe acute respiratory syndrome coronavirus 2 nonstructural protein-1 (Nsp1-CT) inhibits host protein synthesis by blocking messenger RNA (mRNA) access to the 40S ribosome entrance tunnel. Aqueous copper(II) ions bind to the disordered peptide with micromolar affinity, creating a possible strategy to restore protein synthesis during host infection. Electron paramagnetic resonance (EPR) and tryptophan fluorescence measurements on a 10-residue model of the disordered protein region (Nsp1-CT10), combined with advanced quantum mechanics calculations, suggest that the peptide binds to copper(II) as a multidentate ligand. Two optimized computational models of the copper(II)-peptide complexes were derived: One corresponding to pH 6.5 and the other describing the complex at pH 7.5 to 8.5. Simulated EPR spectra based on the calculated model structures are in good agreement with experimental spectra.

Fully activated structure of the sterol-bound Smoothened GPCR-Gi protein complex.

Smoothened (SMO) is an oncoprotein and signal transducer in the Hedgehog signaling pathway that regulates cellular differentiation and embryogenesis. As a member of the Frizzled (Class F) family of G protein-coupled receptors (GPCRs), SMO biochemically and functionally interacts with Gi family proteins. However, key molecular features of fully activated, G protein-coupled SMO remain elusive. We present the atomistic structure of activated human SMO complexed with the heterotrimeric Gi protein and two sterol ligands, equilibrated at 310 K in a full lipid bilayer at physiological salt concentration and pH. In contrast to previous experimental structures, our equilibrated SMO complex exhibits complete breaking of the pi-cation interaction between R4516.32 and W5357.55, a hallmark of Class F receptor activation. The Gi protein couples to SMO at seven strong anchor points similar to those in Class A GPCRs: intracellular loop 1, intracellular loop 2, transmembrane helix 6, and helix 8. On the path to full activation, we find that the extracellular cysteine-rich domain (CRD) undergoes a dramatic tilt, following a trajectory suggested by positions of the CRD in active and inactive experimental SMO structures. Strikingly, a sterol ligand bound to a shallow transmembrane domain (TMD) site in the initial structure migrates to a deep TMD pocket found exclusively in activator-bound SMO complexes. Thus, our results indicate that SMO interacts with Gi prior to full activation to break the molecular lock, form anchors with Gi subunits, tilt the CRD, and facilitate migration of a sterol ligand in the TMD to an activated position.

The mechanism for ligand activation of the GPCR-G protein complex.

G protein­coupled receptors (GPCRs) activate cellular responses ranging from odorants to neurotransmitters. Binding an agonist leads to activation of a heterotrimeric G protein (GP) that stimulates external signaling. Unfortunately, the mechanism remains unknown. We show for 15 class A GPCRs, including opioids, adrenergics, adenosines, chemokines, muscarinics, cannabinoids, serotonins, and dopamines, that interaction of an inactive GP, including Gs, Gi, Go, G11, and Gq, to the inactive GPCR, containing the intracellular ionic lock between transmembrane (TM) helices 3 and 6, evolves exothermically to form a precoupled GPCR-GP complex with an opened TM3-TM6 and the GP-α5 helix partially inserted into the GPCR but not activated. We show that binding of agonist to this precoupled GPCR-GP complex causes the Gα protein to open into its active form, with the guanosine diphosphate exposed for signaling. This GP-first paradigm provides a strategy for developing selective agonists for GPCRs since it is the pharmacophore for the precoupled GPCR-GP complex that should be used to design drugs.

Determining the hydronium pK[Formula: see text] at platinum surfaces and the effect on pH-dependent hydrogen evolution reaction kinetics.

Electrocatalytic hydrogen evolution reaction (HER) is critical for green hydrogen generation and exhibits distinct pH-dependent kinetics that have been elusive to understand. A molecular-level understanding of the electrochemical interfaces is essential for developing more efficient electrochemical processes. Here we exploit an exclusively surface-specific electrical transport spectroscopy (ETS) approach to probe the Pt-surface water protonation status and experimentally determine the surface hydronium pKa [Formula: see text] 4.3. Quantum mechanics (QM) and reactive dynamics using a reactive force field (ReaxFF) molecular dynamics (RMD) calculations confirm the enrichment of hydroniums (H3O[Formula: see text]) near Pt surface and predict a surface hydronium pKa of 2.5 to 4.4, corroborating the experimental results. Importantly, the observed Pt-surface hydronium pKa correlates well with the pH-dependent HER kinetics, with the protonated surface state at lower pH favoring fast Tafel kinetics with a Tafel slope of 30 mV per decade and the deprotonated surface state at higher pH following Volmer-step limited kinetics with a much higher Tafel slope of 120 mV per decade, offering a robust and precise interpretation of the pH-dependent HER kinetics. These insights may help design improved electrocatalysts for renewable energy conversion.

The Reaction Mechanism and Rates at Ru Single-Atom Catalysts for Hydrogenation of Biomass BHMF to Produce BHMTHF for Renewable Polymers.

Realizing high selectivity for producing biodegradable 2,5-bis(hydroxymethyl)tetrahydrofuran (BHMTHF) for renewable polymers from 5-hydroxymethylfurfural (HMF) biomass through ring hydrogenation on single-atom catalysts poses a considerable challenge due to the complexity of HMF functional groups and the difficulty of H2 dissociation. We developed a detailed reaction mechanism based on ab initio molecular dynamics (AIMD) and quantum mechanics (QM) to find that Ru single-atom catalysts can simultaneously dissociate H2 and perform the ring hydrogenation of biomass-derived 2,5-bis(hydroxymethyl)furan (BHMF) to produce biodegradable BHMTHF, with a free energy barrier of 0.82 eV. The unique property of Ru single-atom sites enables H2 to dissociate easily on a single active site of Ru to participate directly in the reaction without diffusion. Furthermore, our predicted reaction rate from microkinetic analysis indicates that ring hydrogenation and side-chain hydrogenolysis are much faster than ring-opening hydrogenation over the range of 300-550 K. The product BHMTHF dominates with a selectivity of 98.9% at 300 and 78.4% at 550 K (the second product is 5-methylfurfural (5-MFA)). This study underscores the unique effectiveness of Ru single atoms in ring hydrogenation reactions using H2 as the hydrogen source, offering insights for the design of single-atom catalysts for other biomass reactions.

The G Protein-First Mechanism for Activation of the Class B Glucagon-like Peptide 1 Receptor Coupled to N-Terminal Domain-Mediated Conformational Progression.

Recently, there has been a great deal of excitement about new glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., semaglutide and tirzepatide) that have received FDA approval for type 2 diabetes and obesity. Although effective, these drugs come with side effects that limit their use. While research efforts continue to focus intensively on long-lasting, orally administered GLP-1R medications with fewer side effects, a major impediment to developing improved GLP-1R medications is that the mechanism by which an agonist activates GLP-1R to imitate signaling is not known. Here we present and validate the G protein (GP)-first mechanism for the GLP-1R supported by extensive atomistic simulations. We propose that GLP-1R is preactivated through the formation of a GLP-1R-GP precoupled complex at the cell membrane prior to ligand binding. Despite a transmembrane helix 6 (TM6)-bentout conformation characteristic of activated GLP-1R, this precoupled complex remains unactivated until an agonist binds to elicit signaling. Notably, this new hypothesis offers a unified and predictive model for the activities of a series of full and partial agonists, including the peptides ExP5, GLP-1(7-36), and GLP-1(9-36). Most surprisingly, our simulations reveal an N-terminus domain (NTD)-swing/agonist-insertion mechanism wherein the long extracellular NTD of GLP-1R tightly holds the C-terminal half of the peptide agonist and progressively shifts the N-terminal head of the peptide to facilitate insertion into the orthosteric pocket. Our findings provide novel mechanistic insights into the activation and function of class B GPCRs and should provide a realistic basis for structure-based ligand design.

How Permanent Are the Permanent Macrodipoles of Anthranilamide Bioinspired Molecular Electrets?

Dipoles are ubiquitous, and their impacts on materials and interfaces affect many aspects of daily life. Despite their importance, dipoles remain underutilized, often because of insufficient knowledge about the structures producing them. As electrostatic analogues of magnets, electrets possess ordered electric dipoles. Here, we characterize the structural dynamics of bioinspired electret oligomers based on anthranilamide motifs. We report dynamics simulations, employing a force field that allows dynamic polarization, in a variety of solvents. The results show a linear increase in macrodipoles with oligomer length that strongly depends on solvent polarity and hydrogen-bonding (HB) propensity, as well as on the anthranilamide side chains. An increase in solvent polarity increases the dipole moments of the electret structures while decreasing the dipole effects on the moieties outside the solvation cavities. The former is due to enhancement of the Onsager reaction field and the latter to screening of the dipole-generated fields. Solvent dynamics hugely contributes to the fluctuations and magnitude of the electret dipoles. HB with the solvent weakens electret macrodipoles without breaking the intramolecular HB that maintains their extended conformation. This study provides design principles for developing a new class of organic materials with controllable electronic properties. An animated version of the TOC graphic showing a sequence of the MD trajectories of short and long molecular electrets in three solvents with different polarities is available in the HTML version of this paper.

CO2-Promoted Electrocatalytic Reduction of Chlorinated Hydrocarbons.

Electrochemical reactions and their catalysis are important for energy and environmental applications, such as carbon neutralization and water purification. However, the synergy in electrocatalysis between CO2 utilization and wastewater treatment has not been explored. In this study, we find that the electrochemical reduction of chlorinated organic compounds such as 1,2-dichloroethane, trichloroethylene, and tetrachloroethylene into ethylene in aqueous media, which is a category of challenging reactions due to the competition of H2 evolution, can be substantially enhanced by simultaneously carrying out the reduction of CO2 on an easily prepared and cost-effective Cu metal catalyst. In the case of 1,2-dichloroethane dechlorination, a 6-fold improvement in Faradaic efficiency and a 19-fold increase in partial current density are demonstrated. Through electrochemical kinetic studies, in situ Raman spectroscopy, and computational simulations, we further find that CO2 reduction reduces hydrogen coverage on the Cu catalyst, which not only exposes more active sites for the dechlorination reaction but also enhances the effective reductive potential on the catalyst surface and reduces the kinetic barrier of the rate-determining step.

Facet-Dependent Oxygen Evolution Reaction Activity of IrO2 from Quantum Mechanics and Experiments.

The diversity of chemical environments present on unique crystallographic facets can drive dramatic differences in catalytic activity and the reaction mechanism. By coupling experimental investigations of five different IrO2 facets and theory, we characterize the detailed elemental steps of the surface redox processes and the rate-limiting processes for the oxygen evolution reaction (OER). The predicted complex evolution of surface adsorbates and the associated charge transfer as a function of applied potential matches well with the distinct redox features observed experimentally for the five facets. Our microkinetic model from grand canonical quantum mechanics (GC-QM) calculations demonstrates mechanistic differences between nucleophilic attack and O-O coupling across facets, providing the rates as a function of applied potential. These GC-QM calculations explain the higher OER activity observed on the (100), (001), and (110) facets and the lower activity observed for the (101) and (111) facets. This combined study with theory and experiment brings new insights into the structural features that either promote or hinder the OER activity of IrO2, which are expected to provide parallels in structural effects on other oxide surfaces.

Molecular Dynamics Investigations of Dienolate [4 + 2] Reactions.

We report quantum mechanics calculations and quasiclassical trajectory simulations of [4 + 2] reactions using three common dienolate substrates: siloxy dienes, Li dienolates, and conjugated Pd enolates. Asynchronous transition structures and unequal bond formation were invariably found, with average time gaps of developing bonds ranging from 26.5 to >251.0 fs. The results display a spectrum of dynamically concerted and stepwise [4 + 2] reactions, offering insights into the origin of the stereochemical outcomes of such reactions.

Modular MPS3-Based Frameworks for Superionic Conduction of Monovalent and Multivalent Ions.

Next-generation batteries based on more sustainable working ions could offer improved performance, safety, and capacity over lithium-ion batteries while also decreasing the cost. Development of next-generation battery technology using "beyond-Li" mobile ions, especially multivalent ions, is limited due to a lack of understanding of solid state conduction of these ions. Here, we introduce ligand-coordinated ions in MPS3-based (M = Mn, Cd) solid host crystals to simultaneously increase the size of the interlayer spacing, through which the ions can migrate, and screen the charge-dense ions. The ligand-assisted conduction mechanism enables ambient temperature superionic conductivity of various next-generation mobile ions in the electronically insulating MPS3-based solid. Without the coordinating ligands, all of the compounds show little to no ionic conductivity. Pulsed-field gradient nuclear magnetic resonance spectroscopy suggests that the ionic conduction occurs through a hopping mechanism, where the cations are moving between H2O molecules, instead of a vehicular mechanism which has been observed in other hydrated layered solids. This modular system not only facilitates tailoring to different potential applications but also enables us to probe the effect of different host structures, mobile ions, and coordinating ligands on the ionic conductivity. This research highlights the influence of cation charge density, diffusion channel size, and effective charge screening on ligand-assisted solid state ionic conductivity. The insights gained can be applied in the design of other ligand-assisted solid state ionic conductors, which will be especially impactful in realizing solid state multivalent ionic conductors. Additionally, the ion-intercalated MPS3-based frameworks could potentially serve as a universal solid state electrolyte for various next-generation battery chemistries.

Enhancing Multifunctionality: Optimal Properties of Iron-Oxide-Reinforced Polyvinylidene Difluoride Unveiled Through Full Atom Molecular Dynamics Simulations.

Nanocomposites made of magnetite (Fe3O4) nanoparticles (NP)s with different surface chemistry and polyvinyl difluoride (PVDF) polymer were investigated using full atom molecular dynamics (MD) simulation. NPs with hydroxyl (OH), hexanoic, and oleic acid terminations were considered in this study. The effect of each surface chemistry was investigated in terms of the mechanical properties, the distribution of the internal energy around the NP, and the chain polarization gradient from the interface to the bulk. From this investigation, we find that oleic acid termination, although the most popular, is less favorable for interfacial interaction and local polarization. The OH-terminated NP results in the best configuration for the properties investigated. The hexanoic acid-grafted NP presents a good compromise. Hydrogen bonding governs the induced response of the nanocomposites. Although the hexanoic acid grafted NP presents less hydrogen bonding than the OH-terminated case, the conformation of the hexanoic acid acts as a mobility flow inhibitor, leading to a performance comparable to that of the OH-terminated NP composite. This work led to investigating routes to make nanocomposite materials with optimized properties. These results shed light on the multiple combinations offered by nanocomposites that go beyond the conventional effects of size.

The spectroscopy of hydride in single crystals of SrTiO3 perovskite.

Under reducing conditions, SrTiO3 perovskite can exchange up to 20% of its O2- ions for H- (hydride), greatly influencing its material properties. This not only presents intriguing possibilities for material design, but also for hydrogen sequestration in the deep earth, where perovskite-structured minerals are abundant. However, uncertainties remain surrounding hydride incorporation in SrTiO3, including details of the hydride structural state, and how hydride interacts with the broader defect chemistry of SrTiO3. Additionally, experimental studies of hydride in SrTiO3 and other perovskites may face analytical limitations. The most common methods for characterizing hydride, namely 1H NMR, may not be suitable in all experimental contexts, including materials with relatively low hydride concentrations and in situ high-pressure, high-temperature experiments. Here, we present an investigation of hydride in single crystals of SrTiO3 focused on detailed spectroscopic measurements. Through a combination of density functional theory (DFT)-assisted Fourier transform infrared (FTIR) spectroscopy and UV-vis spectroscopy, we observe structural hydride and its effects on the electronic transitions in SrTiO3. These results are compared directly against 1H NMR. We find that, although hydride is sometimes difficult to identify via FTIR, infrared spectroscopy is significantly more sensitive to hydride than 1H NMR. We also find that DFT makes accurate predictions about the spectroscopic behavior of hydride in SrTiO3, pointing to the value of ab initio techniques in future studies.

Argentophilic Interactions, Flexibility, and Dynamics of Pyrrole Cages Encapsulating Silver(I) Clusters.

Recently, pyrrole cages have been synthesized that encapsulate ion pairs and silver(I) clusters to form intricate supramolecular capsules. We report here a computational analysis of these structures using density functional theory combined with a semiempirical tight-binding approach. We find that for neutral pyrrole cages, the Gibbs free energies of formation provide reliable predictions for the ratio of bound ions. For charged pyrrole cages, we find strong argentophilic interactions between Ag ions on the basis of the calculated bond indices and molecular orbitals. For the cage with the Ag4 cluster, we find two minimum-geometry conformations that differ by only 6.5 kcal/mol, with an energy barrier <1 kcal/mol, suggesting a very flexible structure as indicated by molecular dynamics. The predicted energies of formation of [Agn⊂1]n-3+ (n = 1-5) cryptands provide low energy barriers of formation of 5-20 kcal/mol for all cases, which is consistent with the experimental data. Furthermore, we also examined the structural variability of mixed-valence silver clusters to test whether additional geometrical conformations inside the organic cage are thermodynamically accessible. In this context, we show that the time-dependent density functional theory UV-vis spectra may potentially serve as a diagnostic probe to characterize mixed-valence and geometrical configurations of silver clusters encapsulated into cryptands.

Detailed Reaction Kinetics for Hydrocarbon Fuels: The Development and Application of the ReaxFFCHO-S22 Force Field for C/H/O Systems with Enhanced Accuracy.

Efficient and accurate reactive force fields (e.g., ReaxFF) are pivotal for large-scale atomistic simulations to comprehend microscopic combustion processes. ReaxFF has been extensively utilized to describe chemical reactions in condensed phases, but most existing ReaxFF models rely on quantum mechanical (QM) data nearly two decades old, particularly in hydrocarbon systems, constraining their accuracy and applicability. Addressing this gap, we introduce a reparametrized ReaxFFCHO-S22 for C/H/O systems, tailored for studying the pyrolysis and combustion of hydrocarbon fuel. Our approach involves high-level QM benchmarks and large database construction for C/H/O systems, global ReaxFF parameter optimization, and molecular dynamics simulations of typical hydrocarbon fuels. Density functional theory (DFT) computations utilized the M06-2X functional at the meta-generalized gradient approximation (meta-GGA) level with a large basis set (6-311++G**). Our new ReaxFFCHO-S22 model exhibits a minimum 10% enhancement in accuracy compared to the previous ReaxFF models for a large variety of hydrocarbon molecules. This advanced ReaxFFCHO-S22 not only enables efficient large-scale studies on the microscopic chemical reactions of more complex hydrocarbon fuel but also can extend to biofuels, energetic materials, polymers, and other pertinent systems, thus serving as a valuable tool for studying chemical reaction dynamics of the large-scale hydrocarbon condensed phase at an atomistic level.

Monolayer atomic crystal molecular superlattices.

Artificial superlattices, based on van der Waals heterostructures of two-dimensional atomic crystals such as graphene or molybdenum disulfide, offer technological opportunities beyond the reach of existing materials. Typical strategies for creating such artificial superlattices rely on arduous layer-by-layer exfoliation and restacking, with limited yield and reproducibility. The bottom-up approach of using chemical-vapour deposition produces high-quality heterostructures but becomes increasingly difficult for high-order superlattices. The intercalation of selected two-dimensional atomic crystals with alkali metal ions offers an alternative way to superlattice structures, but these usually have poor stability and seriously altered electronic properties. Here we report an electrochemical molecular intercalation approach to a new class of stable superlattices in which monolayer atomic crystals alternate with molecular layers. Using black phosphorus as a model system, we show that intercalation with cetyl-trimethylammonium bromide produces monolayer phosphorene molecular superlattices in which the interlayer distance is more than double that in black phosphorus, effectively isolating the phosphorene monolayers. Electrical transport studies of transistors fabricated from the monolayer phosphorene molecular superlattice show an on/off current ratio exceeding 107, along with excellent mobility and superior stability. We further show that several different two-dimensional atomic crystals, such as molybdenum disulfide and tungsten diselenide, can be intercalated with quaternary ammonium molecules of varying sizes and symmetries to produce a broad class of superlattices with tailored molecular structures, interlayer distances, phase compositions, electronic and optical properties. These studies define a versatile material platform for fundamental studies and potential technological applications.

A dynamically equivalent atomistic electrochemical paradigm for the larger-scale experiments.

Electrochemical systems possess a considerable part of modern technologies, such as the operation of rechargeable batteries and the fabrication of electronic components, which are explored both experimentally and computationally. The largest gap between the experimental observations and atomic-level simulations is their orders-of-magnitude scale difference. While the largest computationally affordable scale of the atomic-level computations is ∼ns and ∼nm, the smallest reachable scale in the typical experiments, using very high-precision devices, is ∼s and ∼µm. In order to close this gap and correlate the studies in the two scales, we establish an equivalent simulation setup for the given general experiment, which excludes the microstructure effects (i.e., solid-electrolyte interface), using the coarse-grained framework. The developed equivalent paradigm constitutes the adjusted values for the equivalent length scale (i.e., lEQ), diffusivity (i.e., DEQ), and voltage (i.e., VEQ). The time scale for the formation and relaxation of the concentration gradients in the vicinity of the electrode matches for both smaller scale (i.e., atomistic) equivalent simulations and the larger scale (i.e., continuum) experiments and could be utilized for exploring the cluster-level inter-ionic events that occur during the extended time periods. The developed model could offer insights for forecasting experiment dynamics and estimating the transition period to the steady-state regime of operation.