Metastable Research Articles

Aberrant brain dynamics in major depressive disorder during working memory task.

Working memory (WM) is a distributed and dynamic process, and WM deficits are recognized as one of the top-ranked endophenotype candidates for major depressive disorders (MDD). However, there is a lack of knowledge of brain temporal-spatial profile of WM deficits in MDD. We used the dynamical degree centrality (dDC) to investigate the whole-brain temporal-spatial profile in 40 MDD and 40 controls during an n-back task with 2 conditions (i.e., '0back' and '2back'). We explored the dDC temporal variability and clustered meta-stable states in 2 groups during different WM conditions. Pearson's correlation analysis was used to evaluate the relationship between the altered dynamics with clinical symptoms and WM performance. Compared with controls, under '2back vs. 0back' contrast, patients showed an elevated dDC variability in wide range of brain regions, including the middle frontal gyrus, orbital part of inferior frontal gyrus (IFGorb), hippocampus, and middle temporal gyrus. Furthermore, the increased dDC variability in the hippocampus and IFGorb correlated with worse WM performance. However, there were no significant group-related differences in the meta-stable states were observed. This study demonstrated the increased WM-related instability (i.e., the elevated dDC variability) was represented in MDD, and enhancing stability may help patients achieve better WM performance.

On the Temperature and Composition Dependence of Non‐basal Stacking Faults in C14 Laves Phases

Activation of non‐basal slip is essential in improving the deformability of hexagonal crystals. However, for complex intermetallics such as Laves phase, the mechanism of non‐basal slip remains largely unknown. In this work, the prismatic slip systems of C14 Laves phase crystals and possible metastable states along the slip paths are assessed using atomistic simulations. Multiple prismatic stacking fault states with the same projected positions of atoms but different site occupancies and chemical distributions are identified at different inter‐atomic layers, temperatures and chemical compositions. The formation of energetically favorable prismatic stacking faults involves short‐range diffusion which implies the thermally activated nature of prismatic slip. The outcomes of this work advance the understanding of temperature and composition‐dependent non‐basal slip in Laves phases.

Modeling public opinion control by a charismatic leader

We study the average long-time behavior of the binary opinions of a social group with peer-to-peer interactions under the influence of an external bias and a persuadable leader, a strongly-biased agent with a dynamic opinion with the intention of spreading it across the system. We use a generalized, fully-connected Ising model, with each spin representing the binary opinion of an agent at a given time and a single, super spin representing the opinion of the leader. External fields and interaction constants model the opinion bias and peer-to-peer interactions, respectively, while the temperature T models an idealized social climate, representing an authoritarian regime if T is low or a liberal one if T is high. We derive a mean-field solution for the average magnetization m, the “social mood”, and investigate how m and the super spin magnetization vary as a function of T. We find that, depending on the initial conditions, due to the presence of metastable states, the sign of the average magnetization depends on the temperature. Finally, we verify that this effect is also present even if we consider only nearest-neighbor interactions within the social group.

Adsorption on a Spherical Colloidal Particle from a Mixture of Nanoparticles with Competing Interactions.

Adsorption of nanoparticles on a spherical colloidal particle is studied by molecular dynamics simulations. We consider a generic model for a mixture of nanoparticles with energetically favored self-assembly into alternating layers of the two components. When both components are attracted to the colloidal particle, the adsorbed nanoparticles self-assemble either into alternating parallel tori and clusters at the two poles of the colloidal particle, or into alternating spirals wrapped around the spherical surface. The long-lived metastable states obtained in simulations follow from the spherical shape of the adsorbing surface and the requirement that the neighboring chains of the nanoparticles are composed of different components. A geometrical construction leading to all such patterns is presented. When the second component particles are repelled from the colloidal particle and the attraction of the first component is strong, the attracted particles form a monolayer at the surface of the colloidal particle that screens the repulsion of the second component. The subsequent adsorbed alternating spherical layers of the two components form together a thick shell. This structure leads to the adsorption that is larger than in the case of the same attraction of the two components to the colloidal particle.

Photochemically Driven Peptide Formation in Supersaturated Aerosol Droplets

The condensation of amino acids into peptides plays a crucial role in protein synthesis and is thus essential for understanding the origins of life. However, the spontaneous formation of peptides from amino acids in bulk aqueous media is energetically unfavorable, posing a challenge for elucidating plausible abiotic mechanisms. In this study, we investigate the formation of amide bonds between amino acids within highly supersaturated aerosol droplets containing dicyandiamide (DCD), a cyanide derivative potentially present on primordial Earth. Metastable states, i.e. supersaturation, within individual micron‐sized droplets are studied using both an optical trap and a linear quadrupole electrodynamic balance. When irradiated with intense visible light, amide bond formation is observed to occur and can be monitored using vibrational bands in Raman spectra. The reaction rate is found to be strongly influenced by droplet size and kinetic modelling suggests that it is driven by the photochemical product of a DCD self‐reaction. Our results highlight the potential of atmospheric aerosol particles as reaction environments for peptide synthesis and have potential implications for the prebiotic chemistry of early Earth.

Photochemically Driven Peptide Formation in Supersaturated Aerosol Droplets.

The condensation of amino acids into peptides plays a crucial role in protein synthesis and is thus essential for understanding the origins of life. However, the spontaneous formation of peptides from amino acids in bulk aqueous media is energetically unfavorable, posing a challenge for elucidating plausible abiotic mechanisms. In this study, we investigate the formation of amide bonds between amino acids within highly supersaturated aerosol droplets containing dicyandiamide (DCD), a cyanide derivative potentially present on primordial Earth. Metastable states, i.e. supersaturation, within individual micron-sized droplets are studied using both an optical trap and a linear quadrupole electrodynamic balance. When irradiated with intense visible light, amide bond formation is observed to occur and can be monitored using vibrational bands in Raman spectra. The reaction rate is found to be strongly influenced by droplet size and kinetic modelling suggests that it is driven by the photochemical product of a DCD self-reaction. Our results highlight the potential of atmospheric aerosol particles as reaction environments for peptide synthesis and have potential implications for the prebiotic chemistry of early Earth.

Observation of the liquid metal phase transition in optofluidic microcavities

Gallium (Ga) exhibits remarkable potential in flexible electronics, chemistry, and biomedicine due to its exceptional physical properties. The phase transition and supercooling characteristics of Ga have led to the emergence of numerous valuable applications. In this paper, we capitalize on this foundation by utilizing optofluidic microcavities supporting both high quality factor optical and optomechanical modes to investigate the phase transformation process and supercooling properties of Ga. Our study provides comprehensive insights into the dynamic behavior of Ga during the complete phase transition, such as measuring a hysteresis loop between the solid-to-liquid and liquid-to-solid transitions, revealing nonreciprocal resonance wavelength shift, and identifying a unique metastability state of Ga during melting. The linear thermal expansion coefficients of Ga were precisely measured to be 0.41 × 10−5 K−1 and −0.75 × 10−5 K−1 for solid and liquid Ga, respectively. Our research provides a comprehensive and versatile monitoring platform for newly fabricated liquid metal alloys, offering multidimensional insights into their phase transition behavior.

Unraveling the microscopic origin of out of plane magnetic anisotropy in VI3

Intrinsic two-dimensional (2D) ferromagnetic (FM) semiconductors have attracted extensive attentions for their potential applications in next-generation spintronics devices. In recent years, the van der Waals material VI3 has been experimentally found to be an intrinsic FM semiconductor. However, the electronic structure of the VI3 is not fully understood. To reveal why the VI3 is a ferromagnetic semiconductor with strong out-of-plane anisotropy, we systematically studied the electronic structure of the monolayer VI3. Our results confirm that the monolayer VI3 is a Mott insulator, and d2 electrons occupy ag and egπ+ orbitals. The half-metallic state is a metastable state with a total energy 0.7 eV higher than the ferromagnetic Mott insulating state. Furthermore, our study confirmed that the VI3 exhibits the out-of-plane magnetic anisotropy, which originates from d2 electrons occupying low-lying ag and egπ+ orbitals. Since the orbital angular momentum of the egπ+ state is not completely quenched, the VI3 has the out-of-plane anisotropy under interplay between the spin-orbit coupling and crystal field. Our study provides valuable guidance for the design of 2D magnetic materials with pronounced out-of-plane anisotropy.

Unveiling a common phase transition pathway of high-density amorphous ices through time-resolved x-ray scattering.

Here, we investigate the hypothesis that despite the existence of at least two high-density amorphous ices, only one high-density liquid state exists in water. We prepared a very-high-density amorphous ice (VHDA) sample and rapidly increased its temperature to around 205 ± 10K using laser-induced isochoric heating. This temperature falls within the so-called "no-man's land" well above the glass-liquid transition, wherein the IR laser pulse creates a metastable liquid state. Subsequently, this high-density liquid (HDL) state of water decompresses over time, and we examined the time-dependent structural changes using short x-ray pulses from a free electron laser. We observed a liquid-liquid transition to low-density liquid water (LDL) over time scales ranging from 20ns to 3 μs, consistent with previous experimental results using expanded high-density amorphous ice (eHDA) as the initial state. In addition, the resulting LDL derived both from VHDA and eHDA displays similar density and degree of inhomogeneity. Our observation supports the idea that regardless of the initial annealing states of the high-density amorphous ices, the same HDL and final LDL states are reached at temperatures around 205K.

Meta-stable state photoacid containing β-estradiol fragment with photomodulated biological activity and anti-cancer stem cells properties

Photopharmacology is a young and rapidly developing field of research that offers significant potential for new insights into targeted therapy. While it primarily focuses on cancer treatment, it also holds promise for other diseases. The key feature of photopharmacological agents is the presence of a photosensitive and biologically active component in the same molecule. In our current study, we synthesized a spiropyran-based meta-stable state photoacid containing a fragment of β-estradiol. This compound exhibits negative photochromism and photocontrolled fluorescence under visible-light irradiation due to the initial stabilization of its self-protonated form in solution. We conducted comprehensive biological studies on the HeLa cells model to assess the short- and long-term cytotoxicity of the photoacid, its metabolic effects, its influence on signaling and epithelial-mesenchymal transition super-system pathways, and the proportion of the population enriched with cancer stem cells.Our findings reveal that this derivative demonstrates low cytotoxicity to HeLa cells, yet it is capable of dramatically reducing malignant cells side population enriched in cancer stem cells. Additionally, appropriate structural modification lead to an increase in some other biological effects compared to β-estradiol. In particular, our substance possesses rare properties of AP-1 suppression and demonstrates some pro-oxidant and metabolic effects, which can be regulated by visible light irradiation. As a result, the new estradiol-based photoacid may be considered a promising multi-acting photopharmacological agent for the next-generation anti-cancer research & development.

Automated collective variable discovery for MFSD2A transporter from molecular dynamics simulations

Biomolecules often exhibit complex free energy landscapes in which long-lived metastable states are separated by large energy barriers. Overcoming these barriers to robustly sample transitions between the metastable states with classical molecular dynamics (MD) simulations presents a challenge. To circumvent this issue, collective variable (CV)-based enhanced sampling MD approaches are often employed. Traditional CV selection relies on intuition and prior knowledge of the system. This approach introduces bias, which can lead to incomplete mechanistic insights. Thus, automated CV detection is desired to gain a deeper understanding of the system/process. Analysis of MD data with various machine-learning algorithms, such as principal component analysis (PCA), support vector machine, and linear discriminant analysis (LDA) based approaches have been implemented for automated CV detection. However, their performance has not been systematically evaluated on structurally and mechanistically complex biological systems. Here, we applied these methods to MD simulations of the MFSD2A (Major Facilitator Superfamily Domain 2A) lysolipid transporter in multiple functionally relevant metastable states with the goal of identifying optimal CVs that would structurally discriminate these states. Specific emphasis was on the automated detection and interpretive power of LDA-based CVs. We found that LDA methods, which included a novel gradient descent-based multiclass harmonic variant, termed GDHLDA, we developed here, outperform PCA in class separation, exhibiting remarkable consistency in extracting CVs critical for distinguishing metastable states. Furthermore, the identified CVs included features previously associated with conformational transitions in MFSD2A. Specifically, conformational shifts in transmembrane helix 7 and in residue Y294 on this helix emerged as critical features discriminating the metastable states in MFSD2A. This highlights the effectiveness of LDA-based approaches in automatically extracting from MD trajectories CVs of functional relevance that can be used to drive biased MD simulations to efficiently sample conformational transitions in the molecular system.

Pathways and mechanism of MRTX1133 binding to KRAS G12D elucidated by molecular dynamics simulations and Markov state models

KRAS G12D is the most common oncogenic mutation identified in several types of cancer. Therefore, design of inhibitors targeting KRAS G12D represents a promising strategy for anticancer therapy. MRTX1133 is a highly potent inhibitor (approximate experiment Kd ≈ 0.0002 nM) of KRAS G12D and is currently in Phase 1/2 study, however, pathways of the compound binding to KRAS G12D has remained unknown, and the mechanism underlying the complicated dynamic process are challenging to capture experimentally, which hinder the structure-based anti-cancer drug design. Here, using MRTX1133 as a probe, unbiased molecular dynamics (MD) was used to simulate the process of MRTX1133 spontaneously binding to KRAS G12D. In six of 42 independent MD simulation (a total of 99 μs), MRTX1133 was observed to successfully associate with KRAS G12D. The kinetically metastable states refer to the potential pathways of MRTX1133 binding to KRAS G12D were revealed by Markov state models (MSM) analysis. Additionally, 8 key residues that are essential for MRTX1133 recognition and tight binding at the preferred low energy states were identified by MM/GBSA analysis. In sum, this study provides a new perspective on understanding the pathways and mechanism of MRTX1133 binding to KRAS G12D.

In situ study of phase transformations in the metastable Fe-42Ga alloy

The evolution of the structural phases of the Fe-42.4 at% Ga alloy was studied using neutron diffraction performed with high-intensity continuous scanning in a wide temperature range. The sequence of occurrence of structural states both during heating and subsequent cooling is reported. The structural phases Fe13Ga13, Fe13Ga9, α-Fe6Ga5, D03, L12, A2 are present in the alloy and they disappear upon heating above 800 °C into the partially ordered B2/A2 phase. The high-temperature Fe13Ga13 intermetallic compound exists in two temperature ranges: 25–580 °С and 770–800 °С during heating and precipitates again during cooling. The persistence of the phase upon cooling down to room temperature is inconsistent with the phase diagram, indicating that the alloy remains in a metastable state after the heating and subsequent cooling. The D03, α-Fe6Ga5 and L12 phases are formed during cooling.

Markov State Models Reveal How Folding Kinetics Influence Absorption Spectra of Foldamers.

Self-assembly of platinum(II) complex foldamers is an essential approach to fabricate advanced luminescent materials. However, a comprehensive understanding of folding kinetics and their absorption spectra remains elusive. By constructing Markov state models (MSMs) from large-scale molecular dynamics simulations, we reveal that two largely similar dinuclear alknylplatinum(II) terpyridine foldamers, Pt-PEG and Pt-PE with slightly different bridges, exhibit distinctive folding kinetics. Particularly, Pt-PEG bears bridge-dominant, plane-dominant, and cooperative pathways, while Pt-PE only prefers the plane-dominant pathway. Such preference originates from their difference in intrabridge electrostatic interactions, leading to contrastive distributions of metastable states. We also found that the bridge-dominant pathway for Pt-PEG becomes more favorable when lowering the temperature. Interestingly, based on the comprehensive conformation ensembles from our MSMs, we reveal the conformation-dependent absorption spectra of Pt-PEG and Pt-PE. Our theoretical spectra not only align with experimental results but also reveal the contributions of diverse conformations to the overall absorption bands explicitly, facilitating the rational design of stimuli-responsive smart luminescent molecules.

Nicotine Enantioselectively Targets Myeloid Differentiation Protein 2 and Inhibits the Toll-like Receptor 4 Signaling.

Psychoactive substances, including morphine and methamphetamine, have been shown to interact with the classic innate immune receptor Toll-like receptor 4 (TLR4) and its partner protein myeloid differentiation protein 2 (MD2) in a nonenantioselective manner. (-)-Nicotine, the primary alkaloid in tobacco and a key component of highly addictive cigarettes, targets the TLR4/MD2, influencing TLR4 signaling pathways. Existing as two enantiomers, the stereoselective recognition of nicotine by TLR4/MD2 in the context of the innate immune response remains unclear. In this study, we synthesized (+)-nicotine and investigated its effects alongside (-)-nicotine on lipopolysaccharide (LPS)-induced TLR4 signaling. (-)-Nicotine dose-dependently inhibited proinflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2). In contrast, (+)-nicotine showed no such inhibitory effects. Molecular dynamics simulations revealed that (-)-nicotine exhibited a stronger affinity with the TLR4 coreceptor MD2 than (+)-nicotine. Additionally, in silico simulations revealed that both nicotine enantiomers initially attach to the entrance of the MD2 cavity, creating a metastable state before they fully enter the cavity. In the metastable state, (-)-nicotine established more stable interactions with the surrounding residues at the entrance of the MD2 cavity compared to those of (+)-nicotine. This highlights the crucial role of the MD2 cavity entrance in the chiral recognition of nicotine. These findings provide valuable insights into the distinct interactions between nicotine enantiomers and the TLR4 coreceptor MD2, underscoring the enantioselective effect of nicotine on modulating TLR4 signaling.

Long-term evolution of Ti-Cu amorphous film: Agglomeration and crystallization behaviors of Cu

Sometimes the films deposited by magnetron sputtering are in a metastable state. The films tend to transition to the equilibrium phase, which is crucial for the stability of the microstructure and properties of the films in practical applications. In this study, Ti-Cu films were deposited using a high-power pulsed magnetron sputtering technique, and the evolution of the microstructure of the film under natural aging and thermal aging conditions was systematically investigated. The results showed that the as-deposited Ti-Cu film was amorphous, and as the aging time increased, particles comprising Cu agglomerates and crystalline phases were gradually formed in the film. During aging treatments, Cu agglomerates at the Ti-Cu film led to strong scattering and absorption of the incident light, resulting in reflectance losses. Cu agglomerates at the film was more intense under thermal aging conditions than under natural aging conditions, which was attributed to the fact that the provision of additional temperature could accelerate the diffusion of the smaller Cu atoms in the Ti-Cu amorphous film. Exploring the long-term evolution of the Ti-Cu film structure will provide theoretical guidance for the stability of films in practical applications.

Continuum of metastable helical states of monoaxial chiral magnets: Effect of boundary conditions

Continuum of metastable helical states of monoaxial chiral magnets: Effect of boundary conditions

Detection of metastable solid solution in doped LiFePO4 by synchrotron nuclear resonance techniques

In this work we study one of the popular cathode materials based on doped lithium iron phosphate LiFexMn1-xPO4. Synchrotron operando Mössbauer measurements reveal the existence of metastable states at different stages of the charge and discharge processes, with a lifetime in a wide range from 5 to 140 min. The existence of such states is associated with the formation of a metastable solid solution with the composition LiyFexMn1-xPO4 during cycling. Afterwards, this solution dissolves due to the slow diffusion of manganese and iron ions together with lithium. The presence of metastable states and their rapid decay indicate that cycling is not an equilibrium process. The influence of the manganese migration on the mechanism of the cycling process is discussed in this study.

Mechanical Computing with Transmissive Snapping of Kirigami Shells

AbstractContinuum shape‐morphing structures with the capability to encode memory and execute logic operations have garnered significant interest for the development of mechanical systems with embodied intelligence and soft robots. Achieving the integration of memory and computing within a mechanical system necessitates building blocks that possess a range of tunable, metastable states. Prior efforts have been dedicated to constructing mechanical memory and logic through the exploitation of snap‐through instabilities in multistable structures. Typically, the creation of each logic gate demands a distinct structural design. Here, presents an unconventional design strategy that leverages a single kirigami architecture to perform and switch between multiple fundamental logic operations. By utilizing the kirigami architecture as the fundamental element, mechanical signal transmission is demonstrated and half‐adder computations are performed. It is envisioned that this design strategy can be applied to a wide range of materials and structures, and reduce the complexity of developing materials systems with embodied intelligence.

Prebound State Discovered in the Unbinding Pathway of Fluorinated Variants of the Trypsin-BPTI Complex Using Random Acceleration Molecular Dynamics Simulations.

The serine protease trypsin forms a tightly bound inhibitor complex with the bovine pancreatic trypsin inhibitor (BPTI). The complex is stabilized by the P1 residue Lys15, which interacts with negatively charged amino acids at the bottom of the S1 pocket. Truncating the P1 residue of wildtype BPTI to α-aminobutyric acid (Abu) leaves a complex with moderate inhibitor strength, which is held in place by additional hydrogen bonds at the protein-protein interface. Fluorination of the Abu residue partially restores the inhibitor strength. The mechanism with which fluorination can restore the inhibitor strength is unknown, and accurate computational investigation requires knowledge of the binding and unbinding pathways. The preferred unbinding pathway is likely to be complex, as encounter states have been described before, and unrestrained umbrella sampling simulations of these complexes suggest additional energetic minima. Here, we use random acceleration molecular dynamics to find a new metastable state in the unbinding pathway of Abu-BPTI variants and wildtype BPTI from trypsin, which we call the prebound state. The prebound state and the fully bound state differ by a substantial shift in the position, a slight shift in the orientation of the BPTI variants, and changes in the interaction pattern. Particularly important is the breaking of three hydrogen bonds around Arg17. Fluorination of the P1 residue lowers the energy barrier of the transition between the fully bound state and prebound state and also lowers the energy minimum of the prebound state. While the effect of fluorination is in general difficult to quantify, here, it is in part caused by favorable stabilization of a hydrogen bond between Gln194 and Cys14. The interaction pattern of the prebound state offers insights into the inhibitory mechanism of BPTI and might add valuable information for the design of serine protease inhibitors.