Quantitative insights into the mechanism of proton conduction and selectivity for the human voltage-gated proton channel Hv1.

Human voltage-gated proton (hHv1) channels are crucial for regulating essential biological processes such as immune cell respiratory burst, sperm capacitation, and cancer cell migration. Despite the significant concentration difference between protons and other ions in physiological conditions, hHv1 demonstrates remarkable proton selectivity. Our calculations of single-proton, cation, and anion permeation free energy profiles quantitatively demonstrate that the proton selectivity of the wild-type channel originates from its strong proton affinity via the titration of the key residues D112 and D174, although the channel imposes similar kinetic blocking effects for protons compared to other ions. A two-proton knock-on model is proposed to mathematically explain the electrophysiological measurements of the pH-dependent proton conductance in the conductive state. Moreover, it is shown that the anion selectivity of the D112N mutant channel is tied to impaired proton transport and substantial anion leakage.

Kinetic network modeling with molecular simulation inputs: A proton-coupled phosphate symporter.

Phosphate, an essential metabolite involved in numerous cellular functions, is taken up by proton-coupled phosphate transporters of plants and fungi within the major facilitator family. Similar phosphate transporters have been identified across a diverse range of biological entities, including various protozoan parasites linked to human diseases, breast cancer cells with increased phosphate requirements, and osteoclast-like cells engaged in bone resorption. Prior studies have proposed an overview of the functional cycle of a proton-driven phosphate transporter (PiPT), yet a comprehensive understanding of the proposed reaction pathways necessitates a closer examination of each elementary reaction step within an overall kinetic framework. In this work, we leverage kinetic network modeling in conjunction with a "bottom-up" molecular dynamics approach to show how such an approach can characterize the proton-phosphate co-transport behavior of PiPT under different pH and phosphate concentration conditions. In turn, this allows us to reveal the prevailing reaction pathway within a high-affinity phosphate transporter under different experimental conditions and to uncover the molecular origin of the optimal pH condition of this transporter.

Zero Voltage-Degradation of Li2MnO3 with Ultrathin Amorphous Li─Mn─O Coating.

Manganese-based lithium-rich layered oxides (Mn-LLOs) are promising candidate cathode materials for lithium-ion batteries, however, the severe voltage decay during cycling is the most concern for their practical applications. Herein, an Mn-based composite nanostructure constructed Li2MnO3 (LMO@Li2MnO3) is developed via an ultrathin amorphous functional oxide LixMnOy coating at the grain surface. Due to the thin and universal LMO amorphous surface layer etched from the lithiation process by the high-concentration alkaline solution, the structural and interfacial stability of Li2MnO3 are enhanced apparently, showing the significantly improved voltage maintenance, cycle stability, and energy density. In particular, the LMO@Li2MnO3 cathode exhibits zero voltage decay over 200 cycles. Combining with ex situ spectroscopic and microscopic techniques, the Mn2+/4+ coexisted behavior of the amorphous LMO is revealed, which enables the stable electrochemistry of Li2MnO3. This work provides new possible routes for suppressing the voltage decay of Mn-LLOs by modifying with the composite functional unit construction.

The role of the electrolyte in non-conjugated radical polymers for metal-free aqueous energy storage electrodes.

Metal-free aqueous batteries can potentially address the projected shortages of strategic metals and safety issues found in lithium-ion batteries. More specifically, redox-active non-conjugated radical polymers are promising candidates for metal-free aqueous batteries because of the polymers' high discharge voltage and fast redox kinetics. However, little is known regarding the energy storage mechanism of these polymers in an aqueous environment. The reaction itself is complex and difficult to resolve because of the simultaneous transfer of electrons, ions and water molecules. Here we demonstrate the nature of the redox reaction for poly(2,2,6,6-tetramethylpiperidinyloxy-4-yl acrylamide) by examining aqueous electrolytes of varying chao-/kosmotropic character using electrochemical quartz crystal microbalance with dissipation monitoring at a range of timescales. Surprisingly, the capacity can vary by as much as 1,000% depending on the electrolyte, in which certain ions enable better kinetics, higher capacity and higher cycling stability.

Base-Promoted Annulated Aromatization of Aryl Acetylenes with Dimethyl Sulfoxide to Access Symmetrical/Unsymmetric m-Terphenyl.

A protocol for selective and efficient synthesis of symmetrical and unsymmetrical m-terphenyls is presented among aryl acetylene and DMSO in the presence of KOH and methanol. In this reaction, two molecules of aryl acetylene contribute four carbons, and DMSO, as a dual carbon donor, provides two carbons to a new aromatic ring. This protocol can be tolerated for the electron-donating or disubstituted phenylacetylenes as well as the heterocyclic acetylene derivatives.

Early-Life Exposure to 4-Hydroxy-4'-Isopropoxydiphenylsulfone Induces Behavioral Deficits Associated with Autism Spectrum Disorders in Mice.

Exposure to bisphenol A (BPA) during gestation and lactation is considered to be a potential risk factor for autism spectrum disorder (ASD) in both humans and animals. As a novel alternative to BPA, 4-hydroxy-4'-isopropoxydiphenylsulfone (BPSIP) is frequently detected in breast milk and placental barrier systems, suggesting potential transmission from the mother to offspring and increased risk of exposure. Gestation and lactation are critical periods for central nervous system development, which are vulnerable to certain environmental pollutants. Herein, we investigated the behavioral impacts and neurobiological effects of early-life exposure to BPSIP (0.02, 0.1, and 0.5 mg/kg body weight/day) in mice offspring. Behavioral studies indicated that BPSIP exposure induced ASD-like behaviors, including elevated anxiety-related behavior and decreased spatial memory, in both male and female pups. A distinct pattern of reduced social novelty was observed only in female offspring, accompanied by significant alterations in antioxidant levels. Transcriptome analysis demonstrated that differentially expressed genes (DEGs) were mainly enriched in pathways related to behaviors and neurodevelopment, which were consistent with the observed phenotype. Besides, a decrease in the protein levels of complex IV (COX IV) across all tested populations suggests a profound impact on mitochondrial function, potentially leading to abnormal energy metabolism in individuals with autism. Additionally, changes in synaptic proteins, evidenced by alterations in synapsin 1 (SYN1) and postsynaptic density protein-95 (PSD95) levels in the cerebellum and hippocampus, support the notion of synaptic involvement. These findings suggest that BPSIP may induce sex-specific neurotoxic effects that involve oxidative stress, energy generation, and synaptic plasticity.

Performant automatic differentiation of local coupled cluster theories: Response properties and ab initio molecular dynamics.

In this work, we introduce a differentiable implementation of the local natural orbital coupled cluster (LNO-CC) method within the automatic differentiation framework of the PySCFAD package. The implementation is comprehensively tuned for enhanced performance, which enables the calculation of first-order static response properties on medium-sized molecular systems using coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)]. We evaluate the accuracy of our method by benchmarking it against the canonical CCSD(T) reference for nuclear gradients, dipole moments, and geometry optimizations. In addition, we demonstrate the possibility of property calculations for chemically interesting systems through the computation of bond orders and Mössbauer spectroscopy parameters for a [NiFe]-hydrogenase active site model, along with the simulation of infrared spectra via ab initio LNO-CC molecular dynamics for a protonated water hexamer.

A quantitative paradigm for water-assisted proton transport through proteins and other confined spaces.

Water-assisted proton transport through confined spaces influences many phenomena in biomolecular and nanomaterial systems. In such cases, the water molecules that fluctuate in the confined pathways provide the environment and the medium for the hydrated excess proton migration via Grotthuss shuttling. However, a definitive collective variable (CV) that accurately couples the hydration and the connectivity of the proton wire with the proton translocation has remained elusive. To address this important challenge-and thus to define a quantitative paradigm for facile proton transport in confined spaces-a CV is derived in this work from graph theory, which is verified to accurately describe water wire formation and breakage coupled to the proton translocation in carbon nanotubes and the Cl-/H+ antiporter protein, ClC-ec1. Significant alterations in the conformations and thermodynamics of water wires are uncovered after introducing an excess proton into them. Large barriers in the proton translocation free-energy profiles are found when water wires are defined to be disconnected according to the new CV, even though the pertinent confined space is still reasonably well hydrated and-by the simple measure of the mere existence of a water structure-the proton transport would have been predicted to be facile via that oversimplified measure. In this paradigm, however, the simple presence of water is not sufficient for inferring proton translocation, since an excess proton itself is able to drive hydration, and additionally, the water molecules themselves must be adequately connected to facilitate any successful proton transport.

Key computational findings reveal proton transfer as driving the functional cycle in the phosphate transporter PiPT.

Phosphate is an indispensable metabolite in a wide variety of cells and is involved in nucleotide and lipid synthesis, signaling, and chemical energy storage. Proton-coupled phosphate transporters within the major facilitator family are crucial for phosphate uptake in plants and fungi. Similar proton-coupled phosphate transporters have been found in different protozoan parasites that cause human diseases, in breast cancer cells with elevated phosphate demand, in osteoclast-like cells during bone reabsorption, and in human intestinal Caco2BBE cells for phosphate homeostasis. However, the mechanism of proton-driven phosphate transport remains unclear. Here, we demonstrate in a eukaryotic, high-affinity phosphate transporter from Piriformospora indica (PiPT) that deprotonation of aspartate 324 (D324) triggers phosphate release. Quantum mechanics/molecular mechanics molecular dynamics simulations combined with free energy sampling have been employed here to identify the proton transport pathways from D324 upon the transition from the occluded structure to the inward open structure and phosphate release. The computational insights so gained are then corroborated by studies of D45N and D45E amino acid substitutions via mutagenesis experiments. Our findings confirm the function of the structurally predicted cytosolic proton exit tunnel and suggest insights into the role of the titratable phosphate substrate.

The role of conformational change and key glutamic acid residues in the ClC-ec1 antiporter.

The triple glutamine (Q) mutant (QQQ) structure of a Cl-/H+ antiporter from Escherichia coli (ClC-ec1) displaying a novel backbone arrangement has been used to challenge the long-held notion that Cl-/H+ antiporters do not operate through large conformational motions. The QQQ mutant substitutes the glutamine residue for an external glutamate E148, an internal glutamate E203, and a third glutamate E113 that hydrogen-bonds with E203. However, it is unknown if QQQ represents a physiologically relevant state, as well as how the protonation of the wild-type glutamates relates to the global dynamics. We herein apply continuous constant-pH molecular dynamics to investigate the H+-coupled dynamics of ClC-ec1. Although any large-scale conformational rearrangement upon acidification would be due to the accumulation of excess charge within the protein, protonation of the glutamates significantly impacts mainly the local structure and dynamics. Despite the fact that the extracellular pore enlarges at acidic pHs, an occluded ClC-ec1 within the active pH range of 3.5-7.5 requires a protonated E148 to facilitate extracellular Cl- release. E203 is also involved in the intracellular H+ transfer as an H+ acceptor. The water wire connection of E148 with the intracellular solution is regulated by the charge states of the E113/E203 dyad with coupled proton titration. However, the dynamics extracted from our simulations are not QQQ-like, indicating that the QQQ mutant does not represent the behavior of the wild-type ClC-ec1. These findings reinforce the necessity of having a protonatable residue at the E203 position in ClC-ec1 and suggest that a higher level of complexity exists for the intracellular H+ transfer in Cl-/H+ antiporters.

Reorganization Energy Predictions with Graph Neural Networks Informed by Low-Cost Conformers.

A critical bottleneck for the design of high-conductivity organic materials is finding molecules with low reorganization energy. To enable high-throughput virtual screening campaigns for many types of organic electronic materials, a fast reorganization energy prediction method compared to density functional theory is needed. However, the development of low-cost machine-learning-based models for calculating the reorganization energy has proven to be challenging. In this paper, we combine a 3D graph-based neural network (GNN) recently benchmarked for drug design applications, ChIRo, with low-cost conformational features for reorganization energy predictions. By comparing the performance of ChIRo to another 3D GNN, SchNet, we find evidence that the bond-invariant property of ChIRo enables the model to learn from low-cost conformational features more efficiently. Through an ablation study with a 2D GNN, we find that using low-cost conformational features on top of 2D features informs the model for making more accurate predictions. Our results demonstrate the feasibility of reorganization energy predictions on the benchmark QM9 data set without needing DFT-optimized geometries and demonstrate the types of features needed for robust models that work on diverse chemical spaces. Furthermore, we show that ChIRo informed with low-cost conformational features achieves comparable performance with the previously reported structure-based model on π-conjugated hydrocarbon molecules. We expect this class of methods can be applied to the high-throughput screening of high-conductivity organic electronics candidates.

Multi-site reaction dynamics through multi-fragment density matrix embedding.

The practical description of disordered chemical reactions, where the reactions involve multiple species at multiple sites, is presently a challenge using correlated electronic structure methods due to their high computational cost and steep scaling. Here, we describe the gradient theory of multi-fragment density matrix embedding theory, which potentially provides a minimal computational framework to model such processes at the correlated electron level. We present the derivation and implementation of the gradient theory, its validation on model systems and chemical reactions using density matrix embedding, and its application to a molecular dynamics simulation of proton transport in a small water cluster, a simple example of multi-site reaction dynamics.

Proton coupling and the multiscale kinetic mechanism of a peptide transporter.

Proton-coupled peptide transporters (POTs) are crucial for the uptake of di- and tripeptides as well as drug and prodrug molecules in prokaryotes and eukaryotic cells. We illustrate from multiscale modeling how transmembrane proton flux couples within a POT protein to drive essential steps of the full functional cycle: 1) protonation of a glutamate on transmembrane helix 7 (TM7) opens the extracellular gate, allowing ligand entry; 2) inward proton flow induces the cytosolic release of ligand by varying the protonation state of a second conserved glutamate on TM10; 3) proton movement between TM7 and TM10 is thermodynamically driven and kinetically permissible via water proton shuttling without the participation of ligand. Our results, for the first time, give direct computational confirmation for the alternating access model of POTs, and point to a quantitative multiscale kinetic picture of the functioning protein mechanism.

Resolving the Structural Debate for the Hydrated Excess Proton in Water.

It has long been proposed that the hydrated excess proton in water (aka the solvated "hydronium" cation) likely has two limiting forms, that of the Eigen cation (H9O4+) and that of the Zundel cation (H5O2+). There has been debate over which of these two is the more dominant species and/or whether intermediate (or "distorted") structures between these two limits are the more realistic representation. Spectroscopy experiments have recently provided further results regarding the excess proton. These experiments show that the hydrated proton has an anisotropy reorientation time scale on the order of 1-2 ps. This time scale has been suggested to possibly contradict the picture of the more rapid "special pair dance" phenomenon for the hydrated excess proton, which is a signature of a distorted Eigen cation. The special pair dance was predicted from prior computational studies in which the hydrated central core hydronium structure continually switches (O-H···O)* special pair hydrogen-bond partners with the closest three water molecules, yielding on average a distorted Eigen cation with three equivalent and dynamically exchanging distortions. Through state-of-art simulations it is shown here that anisotropy reorientation time scales of the same magnitude are obtained that also include structural reorientations associated with the special pair dance, leading to a reinterpretation of the experimental results. These results and additional analyses point to a distorted and dynamic Eigen cation as the most prevalent hydrated proton species in aqueous acid solutions of dilute to moderate concentration, as opposed to a stabilized or a distorted (but not "dancing") Zundel cation.

Structural Characterization of Protonated Water Clusters Confined in HZSM-5 Zeolites.

A molecular description of the structure and behavior of water confined in aluminosilicate zeolite pores is a crucial component for understanding zeolite acid chemistry under hydrous conditions. In this study, we use a combination of ultrafast two-dimensional infrared (2D IR) spectroscopy and ab initio molecular dynamics (AIMD) to study H2O confined in the pores of highly hydrated zeolite HZSM-5 (∼13 and ∼6 equivalents of H2O per Al atom). The 2D IR spectrum reveals correlations between the vibrations of both terminal and H-bonded O-H groups and the continuum absorption of the excess proton. These data are used to characterize the hydrogen-bonding network within the cluster by quantifying single-, double-, and non-hydrogen-bond donor water molecules. These results are found to be in good agreement with the statistics calculated from an AIMD simulation of an H+(H2O)8 cluster in HZSM-5. Furthermore, IR spectral assignments to local O-H environments are validated with DFT calculations on clusters drawn from AIMD simulations. The simulations reveal that the excess charge is detached from the zeolite and resides near the more highly coordinated water molecules in the cluster. When they are taken together, these results unambiguously assign the complex IR spectrum of highly hydrated HZSM-5, providing quantitative information on the molecular environments and hydrogen-bonding topology of protonated water clusters under extreme confinement.

Deactivation-free ethanol steam reforming at nickel-tipped carbon filaments.

Ni based catalysts have been widely studied for H2 production due to the ability of Ni to break C-C and C-H bonds. In this work, we study inverse catalysts prepared by well-controlled sub-monolayer deposition of CeO2 nanocubes onto Ni thin films for ethanol steam reforming (ESR). Results show that controlling the coverage of CeO2 nanocubes on Ni enhances H2 production by more than an order of magnitude compared to pure Ni. Contrary to the idea that C deposits must be continuously oxidized for sustained H2 production, the surface of the most active catalysts show significant C deposition, yet no deactivation is observed. HAADF-STEM analysis reveals the formation of carbon filaments (CFILs), which propel Ni particles upward at the filament tips via a catalytic tip growth mechanism, resulting in a Ni@CFIL active phase for ESR. Near-ambient pressure XPS indicates that the Ni@CFIL active phase forms as a result of C gradients at the interface between regions of pure Ni metal and domains of closely packed CeO2 nanocubes. These results show that the mesoscale morphology of deposited CeO2 nanocubes is responsible for templating the formation of a Ni@CFIL catalyst, which resists deactivation leading to highly active and stable H2 production from ethanol.

The hopping mechanism of the hydrated excess proton and its contribution to proton diffusion in water.

In this work, a series of analyses are performed on ab initio molecular dynamics simulations of a hydrated excess proton in water to quantify the relative occurrence of concerted hopping events and "rattling" events and thus to further elucidate the hopping mechanism of proton transport in water. Contrary to results reported in certain earlier papers, the new analysis finds that concerted hopping events do occur in all simulations but that the majority of events are the product of proton rattling, where the excess proton will rattle between two or more waters. The results are consistent with the proposed "special-pair dance" model of the hydrated excess proton wherein the acceptor water molecule for the proton transfer will quickly change (resonate between three equivalent special pairs) until a decisive proton hop occurs. To remove the misleading effect of simple rattling, a filter was applied to the trajectory such that hopping events that were followed by back hops to the original water are not counted. A steep reduction in the number of multiple hopping events is found when the filter is applied, suggesting that many multiple hopping events that occur in the unfiltered trajectory are largely the product of rattling, contrary to prior suggestions. Comparing the continuous correlation function of the filtered and unfiltered trajectories, we find agreement with experimental values for the proton hopping time and Eigen-Zundel interconversion time, respectively.

Effects of electromagnetic waves on oocyte maturation and embryonic development in pigs.

Our living environment has been full of electromagnetic radiation (EMR) due to the prevailing electronic devices and equipment. Intermediate frequency electromagnetic field (IF-EMF) or waves constitute a significant part of EMR; therefore, an increasing number of household electrical appliances have become a source of IF-EMF, and concerns about IF-EMF on health are gaining more attention. However, little information is available about its impact on female reproductive traits, such as germ cell viability and early embryonic development, particularly at the cellular and molecular levels. In this study, we used porcine oocytes as a model system to explore the effect of IF-EMF at various intensities on the in vitro maturation (IVM) of oocytes and their subsequent embryonic development. Our results showed that no difference in oocyte maturation rates was detected among groups, but the cleavage and blastocyst rates of parthenotes derived from EMF-treated oocytes decreased with the weaker IF-EMF intensity (25 and 50 Gauss) groups compared to the control group (P < 0.05). For cytoplasmic maturation, the weaker IF-EMF intensity groups also showed a peripheral pattern of mitochondrial distribution resembling that of immature oocytes and increased autophagy activity. No obvious differences in cytoskeletal distribution and total cell numbers of blastocysts were investigated in the four IF-EMF treatments compared to those in the control group. Although the underlying mechanism associated with EMF effects on oocytes and embryos is still elusive, we have demonstrated that low intensity IF-EMF exerts harmful effects on porcine oocytes during the maturation stage, carrying over such effects to their subsequent embryonic development.

Duck Eggshell Crack Detection by Nondestructive Sonic Measurement and Analysis.

Duck eggs are a good source of essential nutrients for the human body. However, transportation, processing, and handling can easily cause cracks in the eggshells. These cracks can lead to microbial contamination, reducing the shelf life and compromising food safety. In this study, a method for the nondestructive testing of cracks in duck eggshells was developed. First, the acoustic emission signals of intact and cracked eggshells were measured, and the most significant frequency features were selected to establish a calibration curve for cracked eggshells. Logistic regression using the frequency features was then adopted to predict intact and cracked eggshells. Then, we establish a set of optimal regression models and used independent samples for verification. The overall accuracy rates of the calibration and prediction models using five frequencies of bandwidth (1500, 5000, 6000, 8500, and 10,000 Hz) were 89.7% and 87.6%, respectively. Sound measurement enables a simple and quantitative method for duck egg crack detection and classification. This nondestructive and cost-effective method can be used for duck egg quality screening and can be integrated into duck egg processing machinery.

Multiscale Simulation Reveals Passive Proton Transport Through SERCA on the Microsecond Timescale.

The sarcoplasmic reticulum Ca2+-ATPase (SERCA) transports two Ca2+ ions from the cytoplasm to the reticulum lumen at the expense of ATP hydrolysis. In addition to transporting Ca2+, SERCA facilitates bidirectional proton transport across the sarcoplasmic reticulum to maintain the charge balance of the transport sites and to balance the charge deficit generated by the exchange of Ca2+. Previous studies have shown the existence of a transient water-filled pore in SERCA that connects the Ca2+ binding sites with the lumen, but the capacity of this pathway to sustain passive proton transport has remained unknown. In this study, we used the multiscale reactive molecular dynamics method and free energy sampling to quantify the free energy profile and timescale of the proton transport across this pathway while also explicitly accounting for the dynamically coupled hydration changes of the pore. We find that proton transport from the central binding site to the lumen has a microsecond timescale, revealing a novel passive cytoplasm-to-lumen proton flow beside the well-known inverse proton countertransport occurring in active Ca2+ transport. We propose that this proton transport mechanism is operational and serves as a functional conduit for passive proton transport across the sarcoplasmic reticulum.