Pemetrexed acts as a PPAR γ partial agonist via a unique binding mode that avoids AF-2 engagement, providing a structural basis for designing novel dual-pathway inhibitors for NSCLC therapy.

Abstract Heteromeric amino acid transporters (HATs) mediate essential amino acid flux across membranes, but the molecular dynamics of substrate translocation remain poorly defined for many family members. Here, using conventional and adaptive steered molecular dynamics (cMD and ASMD) simulations, we identify residue W230 in the b 0,+ AT transport channel as a dynamic gate that regulates arginine (Arg) influx through side chain flipping. By integrating dynamic network analysis with dynamical cross-correlation of residue motions, we show that regulatory signals propagate from the Arg binding site through transmembrane helix 5 (TM5), a connecting loop, and TM6 to reach W230. We propose a dynamic gating mechanism for b 0,+ AT - mediated amino acid transport. Arg binding at V186 triggers signal propagation that enhances cooperative interactions between W230 and Arg, driving the side chain flipping of W230. Our findings reveal a dynamic gating mechanism underlying b 0,+ AT - dependent Arg transport and suggest that residue-triggered side chain reorientation may represent a conserved and efficient strategy in transporter function. Author Summary Amino acids are the essential building blocks of life, and their transport across cell membranes is vital for nutrition and cellular signaling. Heteromeric amino acid transporters (HATs) mediate this process, yet how they physically move substrates through the protein at the atomic level remains poorly understood. In this study, we used advanced computer simulations to observe, in unprecedented detail, how b 0,+ AT—a key HAT member—transports the amino acid arginine. Our simulations revealed that a single residue, tryptophan 230 (W230), functions as a molecular gate: its side chain flips open to allow arginine to pass and then closes behind it, ensuring one-way traffic into the cell. We further discovered that the initial binding of arginine sends a signal through specific structural elements (helices and loops) to trigger this gate opening. This work not only uncovers a dynamic gating mechanism for b 0,+ AT but also suggests that similar side-chain flipping events may represent a common and efficient strategy used by other transporters to control substrate movement. Our findings provide a new framework for understanding transporter function and could inform future drug design targeting these critical membrane proteins.

Ambipolar semiconductors based on two-dimensional p-n junctions have attracted significant attention and are driving optoelectronic and logic circuit applications. However, their low carrier mobility and electron-hole mobility asymmetry (>10(1)) result in poor signal resolution, which limits its practical applications. This study demonstrates high-mobility and mobility-symmetric ambipolar transport in MoS2/WSe2 p-n heterojunctions through precise oxygen plasma-mediated interface engineering. The mild oxygen plasma treatment simultaneously passivates selenium vacancies in WSe2 and sulfur vacancies in MoS2, thereby reducing scattering centers and optimizing carrier concentrations. The elevated and balanced carrier concentrations on both sides of the junction effectively lower the tunneling barrier, facilitating efficient charge injection and enabling high-performance ambipolar conduction. Analysis of the charge transport mechanism reveals a direct tunneling mode at the heterointerface. By applying a 6 s low-power soft oxygen plasma treatment to MoS2 and a 30 s oxygen plasma to WSe2, the device exhibits a more than two orders of magnitude improvement in electrical performance, demonstrating symmetric ambipolar behavior with a hole mobility of 83 cm(2) V-1 s(-1) and an electron mobility of 42 cm(2) V-1 s(-1), respectively. This work establishes plasma-induced design principles for high-performance ambipolar transistors and provides critical insights for logic optoelectronic devices.

Understanding the origin of ultralow lattice thermal conductivity (kappa(L)) in crystals is crucial for the development of advanced thermoelectric and thermal management materials. This study systematically investigates thermal transport mechanisms in perovskite CsPbBr3 crystals using a novel framework that integrates quartic anharmonicity-driven phonon spectral renormalization at finite temperatures with machine learning potential-driven molecular dynamics. In contrast to results from ground-state anharmonic lattice dynamics, our findings reveal that the ultralow kappa(L) in CsPbBr3 predominantly arises from particle-like phonon propagation rather than wave-like phonon coherence, due to anharmonic renormalization shifting most phonon modes from the Wigner limit into the propagation regime. Furthermore, the temperature-dependent quartic anharmonicity effectively promotes particle-like while limiting wave-like phonon transport channels, accurately reproducing the experimental ultralow kappa(L) of CsPbBr3 in magnitude and temperature dependence. This study not only resolves the discrepancy between measured and predicted kappa(L) in CsPbBr3 crystals but also reveals the dominant role of particle-like phonon propagation in flat ultralow kappa(L), providing a revised physical picture for understanding anharmonic thermal transport and critical insights for regulating kappa(L) of materials through lattice anharmonicity.

Transition-metal compounds with strong spin-orbit coupling (SOC) have attracted significant attention due to their potential for hosting exotic magnetic states such as frustrated magnetism, as well as their promising optoelectronic applications in hybrid halides. In these systems, the pronounced SOC effects often lead to magnetic behaviors that can not be adequately described by the standard Curie-Weiss law. In this review, based on our recent investigations, we summarize progress on the temperature evolution of magnetic susceptibilities and magnetic moments in SOC-driven systems. We first outline the general background. Using perovskite compounds as representative examples, we then systematically introduce the microscopic origin of the temperature dependence of magnetic susceptibilities for d(1)-d(5) electronic configurations. We further discuss the evolution of magnetic moments and susceptibilities in systems based on magnetic clusters, such as dimers or trimers, and introduce modified Curie-Weiss fitting approaches that account for the temperature dependence of magnetic moments. Finally, we summarize current research trends and offer an outlook on potential future developments in this field.

Van der Waals (vdW) heterostructures, typically composed of two-dimensional (2D) atomic layers, have attracted significant attention over the past few decades. Their performance is closely dependent on their composition and interlayer interactions. In this study, we constructed four types of 2D hexagonal BP monolayer (h-BP)/borophosphene vdW heterostructures with different stacking orders: (i) B-B stacking, (ii) P-P stacking, (iii) moire-I, and (iv) moire-II. Their structural stability and their electronic and optical properties were explored by using first-principles calculations. The results show that h-BP/borophosphene heterostructures can maintain their configurations with good structural stability and minimal lattice mismatch. All vdW heterostructures exhibit semiconducting characteristics, and their band gaps are highly dependent on interlayer stacking orders. Due to the regular atomic arrangement and enhanced interlayer dipole interactions, the B-B stacking bilayer opens a relatively large band gap of 0.157 eV, while the moire-II bilayer exhibits a very small band gap of 0.045 eV because of its irregular atom arrangements. By calculating the complex dielectric function, optical absorption spectra of B-B and P-P stacking bilayers were discussed. This study suggests that h-BP/borophosphene heterostructures have desirable optical properties, broadening the potential applications of the constituent monolayers.

We introduce an exactly solvable lattice model that reveals a universal finite-size scaling law for configurational entropy driven purely by geometry. Using exact enumeration via Burnside's lemma, we compute the entropy for diverse 1D, 2D, and 3D lattices, finding that the deviation from the thermodynamic limit s_∞ = ln (z) scales as Δs_N∼ N^-1/d, with lattice-dependent higher-order corrections. This scaling, observed across structures from chains to FCC and diamond lattices, offers a minimal framework to quantify geometric influences on entropy. The model captures the order of magnitude of experimental residual entropies (e.g., S_molar = R ln 12 ≈ 20.7 J/mol · K) and provides a reference for understanding entropy-driven order in colloids, clusters, and solids.

The TFIIS N-terminal domain (TND) is a crucial protein scaffold that selectively recognizes disordered ligands, known as TND-interacting motifs (TIMs). Understanding the specific mechanisms of TND-TIM interactions is essential for deciphering the transcription machinery. Here, we investigated the conformational ensembles of the TND-TIM interaction module using molecular dynamics simulations. The study revealed that the experimental structures of TND-TIM complexes, including P75-PogZ and P75-IWS1, maintained stable conformations during microsecond-long simulations, even when the linked proteins between TND and TIM were removed or when TIM was phosphorylated. Conversely, both P75-ASK and HRP2-IWS1, prepared based on the structure of P75-IWS1, are unstable in simulations; for example, the helix-1 of TIMs shifts from their initial binding site on TND. However, phosphorylation enhances TND-TIM interactions and rapidly stabilizes the complex structure. A general rule for phosphorylation regulation of TND-TIM interactions is identified: the phosphoryl group of TIM forms hydrogen bonds with the positively charged side chains of TND residues, promoting dynamic correlation between TND and the Ser-containing acidic linker of TIM, and enhancing residue-residue interactions among helix-1 and FXGF motif of TIM with TND. These phosphorylation-induced changes resulted in a higher affinity between TND and TIM. Our study provides insights into the phosphorylation-regulated TND-TIM interaction module at an atomic level, facilitating a deeper understanding of the molecular mechanisms of protein interactome assembly in transcription machinery.

Anti-inflammatory peptides (AIPs) have emerged as potential therapeutic candidates for managing various inflammatory disorders, but their computational identification remains challenging. We propose AIP-TranLAC, a novel deep learning framework that integrates Transformer-based embedding, bidirectional long short-term memory (Bi-LSTM), multi-head attention, and convolutional neural network (CNN) to classify AIPs accurately. Our model achieves superior performance on benchmark and independent test datasets, demonstrating significant improvements over existing methods. The hybrid architecture effectively captures local and global sequence patterns, while interpretability analyses reveal critical amino acid residues. With robust performance on imbalanced data and open-source availability, AIP-TranLAC provides a powerful tool for accelerating therapeutic peptide discovery and inflammation research. For reproducibility purposes, we have released the codebase, trained models, and all supporting data on GitHub ( https://github.com/Renjingyi123/AIP-TranLAC ).

The negative differential transconductance (NDT) effect has recently attracted attention due to its possible application in multi-valued logic (MVL) devices. However, current research is based on the stacked van der Waals heterojunctions composed of two materials to realize a single-peak NDT effect. Complex transistor structures and low electrical performance limit practical applications in MVL devices. In this study, the NDT effect with a high peak current is demonstrated in a simple structured WSe2 field effect transistor. After oxygen plasma treatment, the upper layer WSe2 changes into WO3-x. The NDT effect is observed at gate voltage sweeps from negative to positive values, and is attributed to the competition of two factors. On the one hand, the slow oxygen migration in the top layer WO3-x leads to a continuous increase of carriers in the channel. On the other hand, the reduction of electrical field induced by gate voltage leads to a decrease of the carrier concentration in the channel. It is the competition that leads to the emergence of the NDT phenomenon and a high peak current (similar to 200 mu A). In a word, we realize a high peak current NDT effect in a transistor with easy-to-prepare structures. This study paves the way for achieving enhanced signal resolution in MVL devices.

The catalysts of transition metal single-atom embedded in N-doped graphene (TMN4-Gr) have attracted significant attention due to the high utilization of transition metal atoms, remarkable selectivity and tunable catalytic activity. In this study, we have employed first-principles study to investigate alkaline oxygen evolution reaction (OER) activity of FeN4-Gr system supported on a Ni (111) substrate (FeN4-Gr/Ni). The results show that the Ni substrate can significantly enhance the OER activity of FeN4-Gr catalyst. The overpotential of FeN4-Gr/Ni catalyst is 0.63 V, much lower than 0.79 V of the FeN4-Gr, which is closely related to the strong interaction from the Ni substrate. By subtracting electrons from the FeN4-Gr/Ni catalyst, a positive charge environment can be created. It is found that, between the FeN4-Gr and the Ni substrate, a significant electron transfer phenomenon is observed, and the amount can be regulated by the charge state. Besides, the charge state can obviously tune the adsorption strength of *OOH intermediate through the interaction of Ni substrate, further optimizing the OER activity thermodynamically favorable. As the charge state increases to +1.55, the overpotential decreases to 0.23 V. By analyzing the integrated crystal orbital Hamilton populations, the chemical bond strength of Fe-O is discussed. Our results reveal that the Ni substrate can significantly enhance the OER activity of the FeN4-Gr catalyst, and the charge state can also tune the overpotential, offering valuable insights for the design of high-efficiency single-atom catalysts utilizing metal substrate.

Ferromagnetism, as one of the most valuable properties of materials, has attracted sustained and widespread interest in basic and applied research from ancient compasses to modern electronic devices. Traditionally, intrinsic ferromagnetism has been attributed to the permanent magnetic moment induced by partially filled d- or f-orbitals. However, the development of ferromagnetic materials has been limited by this electronic structure convention. Thus, the identification of additional materials that are not constrained by this conventional rule but also exhibit intrinsic ferromagnetism is highly expected and may impact all the fields based on ferromagnetism. Here, we report the direct observation of room-temperature intrinsic ferromagnetism in two-dimensional (2D) Na2Cl crystals, in which there are only partially filled s- and p-orbitals rather than d- or f-orbitals, using the superconducting quantum interference device (SQUID) and magnetic force microscope (MFM). These Na2Cl crystals formed in reduced graphene oxide (rGO) membranes have an unconventional stoichiometric structure leading to unique electron and spin distributions. And the structure of these 2D Na2Cl crystals, including the Na and Cl sites, is characterized in situ for the first time and directly observed by cryo-electron microscopy (cryo-EM) based on the observed difference in contrast between Na stacked with Cl and single Na. These findings break the conventional rule of intrinsic ferromagnetism and provide new insights into the design of novel magnetic and electronic devices and transistors with a size down to the atomic scale.

Enhancing the phase transition reversibility of electrode materials is an effective strategy to alleviate capacity degradation in the cycling of lithium-ion batteries (LIBs). However, a comprehensive understanding of phase transitions under microscopic electrode dynamics is still lacking. In this paper, the activation polarization is quantified as the potential difference between the applied potential (Uabs) and the zero-charge potential (ZCP) of electrode materials. The polarization potential difference facilitates the phase transition by driving Li-ion adsorption and supplying an electron-rich environment. A novel thermodynamic phase diagram is constructed to characterize the phase transition of the example MoS2 under various Li-ion concentrations and operating voltages using the grand canonic fixed-potential method (FPM). At thermodynamic quasi-equilibrium, the ZCP is close to the Uabs, and thus is used to form the discharge curve in the phase diagram. The voltage plateau is observed within the phase transition region in the simulation, which will disappear as the phase transition reversibility is impaired. The obtained discharge curve and phase transition concentration both closely match the experimental results. Overall, the study provides a theoretical understanding of how polarization affects phase evolution in electrode dynamics, which may provide a guideline to improve battery safety and cycle life.

Nozi & egrave;res' exhaustion theory argues that the temperature for coherently screening of all local moments in Kondo lattice could be much lower than the temperature of single moment screening in case of insufficient conduction electrons. Experiments indicate that cerium based nickel pnictides CeNi2-delta As2(delta approximate to 0.28) is an ideal material to exam such protracted Kondo screening. Using density functional theory plus dynamical mean-field theory, we found CeNi2As2 presents a transition from the local moment states to the coherent Kondo screening states under compression, accompanied by topological changes of the Fermi surface. Similar phase transition could be driven by chemical pressure via the isovalence As -> P substitution. The derived coherent Kondo temperature T-coh is much lower than the single-impurity Kondo temperature T(K )due to the diluted Ni-3d conduction electrons, indicating the protraction of Kondo screening in crystal. In contrast to structurally analogous layered iron pnictides, the electronic structures of the present systems show strong three-dimensionality.

Alzheimer’s disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the fundamental molecular mechanism underlying their pathological association. The green tea extract epigallocatechin-3-gallate (EGCG) has been extensively demonstrated to inhibit the amyloid aggregation of Aβ and hIAPP proteins. However, its potential role in amyloid co-aggregation has not been thoroughly investigated. In this study, we employed the enhanced-sampling replica exchange molecular dynamics simulation (REMD) method to investigate the effect of EGCG on the co-aggregation of Aβ and hIAPP. We found that EGCG molecules substantially diminish the β-sheet structures within the amyloid core regions of Aβ and hIAPP in their co-aggregates. Through hydrogen-bond, π–π and cation–π interactions targeting polar and aromatic residues of Aβ and hIAPP, EGCG effectively attenuates both inter-chain and intra-chain interactions within the co-aggregates. All these findings indicated that EGCG can effectively inhibit the co-aggregation of Aβ and hIAPP. Our study expands the potential applications of EGCG as an anti-amyloidosis agent and provides therapeutic options for the pathological association of amyloid misfolding disorders.

Simultaneously improving activity and stability is a crucial yet challenge in the development of metallic single-atom-based catalysts. In current work, a novel approach is introduced to address this issue by combining post-adsorption and secondary pyrolysis techniques to create a synergistic catalytic system, in which the single atoms (SAs) Fe sites played in the NC matrix (Fe & horbar;NC) are coupled with high-entropy atomic clusters (HEACs). Theoretical calculations reveal that the incorporation of HEACs lead to a rehybridization of the 3d orbital configuration of Fe-N-4, which helps to balance the adsorption/desorption energy of oxygenated intermediates. In situ spectroscopy further reveals that the rate-limiting step of OH* desorption on HEAC/Fe & horbar;NC in oxygen reduction reaction (ORR) is more facile compared to atomic Fe & horbar;NC, implying a higher ORR activity. Moreover, the synergistic effect of diffusion activation barriers and configuration entropy contributes to the structural stability of HEAC/Fe & horbar;NC, resulting in remarkable durability. Consequently, this unique catalyst exhibits half-wave potentials of 0.927 and 0.828 V in an aqueous solution of KOH (0.1 m) and HClO4 (0.1 m), respectively, along with excellent durability. The findings propose a novel strategy for modulating the electronic structure of metallic SAs catalysts and enhancing their stability through strong interactions between SAs and HEACs.

Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor involved in metabolic processes, inflammation, and energy balance, represents a promising therapeutic target for cardiovascular diseases. Danshensu Bingpian Zhi (DBZ), a chiral compound derived from traditional Chinese medicine, exhibits potential as a PPARγ agonist. Using an ensemble-based docking approach, molecular dynamics (MD) simulations, and the molecular mechanics generalized born surface area (MM/GBSA) methods, we explored the binding modes and energetics of DBZ stereoisomers with the PPARγ ligand-binding domain (LBD). The results indicated that the right-handed stereoisomer (DBZR) binds like a full agonist, while the left-handed stereoisomer (DBZS) binds as a partial agonist with stronger binding energies (ΔGbind), indicating a robust interaction with PPARγ. Both the stereoisomers stabilize the β-sheet region of PPARγ-LBD, potentially protecting Ser245 from phosphorylation by Cdk5, a process implicated in atherosclerosis. Principal component analysis (PCA) and dynamic cross-correlation matrices (DCCM) revealed the complex structural dynamics within the Ω loop, β-sheet, and AF-2 region of PPARγ-LBD upon ligand binding, which may contribute to the unique binding mode and efficacy of DBZS. These findings provide insights into the molecular recognition of PPARγ-LBD by DBZ stereoisomers and their impact on the conformational dynamics of PPARγ, highlighting the therapeutic potential of DBZ and the significance of chirality in drug design.

While undergoing structural deformation, DNA experiences changes in the interactions between its internal base pairs, presenting challenges to conventional elastic methods. To address this, we propose the Discrete Critical State (DCS) model in this paper. This model combines surface discrete frame theory with gauge theory and Landau phase transition theory to investigate DNA’s structural deformation, phase transitions, and chirality. Notably, the DCS model considers both the internal interactions within DNA and formulates an overall equation using unified physical and geometric parameters. By employing the discrete frame, we derive the evolution of physical quantities along the helical axis of DNA, including geodesic curvature, geodesic torsion, and others. Our findings indicate that B-DNA has a significantly lower free energy density compared to Z-DNA, which is in agreement with experimental observations. This research reveals that the direction of base pairs is primarily governed by the geodesic curve within the helical plane, aligning closely with the orientation of the base pairs. Moreover, the geodesic curve has a profound influence on the arrangement of base pairs at the microscopic level and effectively regulates the configuration and geometry of DNA through macroscopic-level free energy considerations.

The structural diversity of biological macromolecules in different environments contributes complexity to enzymological processes vital for cellular functions. Fluorescence resonance energy transfer and electron microscopy are used to investigate the enzymatic reaction of T4 DNA ligase catalyzing the ligation of nicked DNA. The data show that both the ligase-AMP complex and the ligase-AMP-DNA complex can have four conformations. This finding suggests the parallel occurrence of four ligation reaction pathways, each characterized by specific conformations of the ligase-AMP complex that persist in the ligase-AMP-DNA complex. Notably, these complexes have DNA bending angles of ≈0°, 20°, 60°, or 100°. The mechanism of parallel reactions challenges the conventional notion of simple sequential reaction steps occurring among multiple conformations. The results provide insights into the dynamic conformational changes and the versatile attributes of T4 DNA ligase and suggest that the parallel multiple reaction pathways may correspond to diverse T4 DNA ligase functions. This mechanism may potentially have evolved as an adaptive strategy across evolutionary history to navigate complex environments.

The discovery of ferromagnetism in van der Waals materials attracts intense research interest and holds profound implications for two-dimensional spintronic devices. However, in most cases the Curie temperature of van der Waals ferromagnets is much lower than room temperature, hindering their potential for device applications. In this study we report the discovery of room-temperature ferromagnetism in layered Ta 0 . 67 V 0 . 33 Se 2 . The single crystal is synthesized through the partial replacement of tantalum with vanadium. The crystal structure of Ta 0 . 67 V 0 . 33 Se 2 closely resembles that of both 1T-VSe2 and 1T-TaSe2. The resultant Ta 0 . 67 V 0 . 33 Se 2 exhibits a Hall sign reversal at around 60 K, with the dominant carrier changing from electron type at higher temperatures to hole type at lower temperatures. The anomalous peak is observed in the longitudinal resistivity near the critical temperature, which is ascribed to the temperature-induced Lifshitz transition. Despite the fact that bulk 1T-VSe2 and 1T-TaSe2 are paramagnetic, Ta 0 . 67 V 0 . 33 Se 2 displays room-temperature ferromagnetism, as evidenced by the hysteresis behavior observed in the field-dependent magnetization. Collective anomalies are observed at about 60 K in both magnetization and transport measurements, indicating a strong correlation between electric and magnetic degrees of freedom. Moreover, room-temperature ferromagnetism is confirmed in few-layer Ta 0 . 67 V 0 . 33 Se 2 through magneto-optic Kerr measurements. Our work provides a strategy for accessing two-dimensional high-Curie-temperature magnets, which hold promise for potential applications in spintronic devices.