Experimental Molecular Dynamics Research Articles

Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice.

Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine's physicochemical and therapeutic properties. We showed that piplartine had a wide therapeutic window and neither induced nephrotoxicity in vivo in zebrafish nor interfered with aminoglycoside antibacterial activity. In addition, a fluorescence-based assay demonstrated that piplartine did not inhibit cytochrome C activity in microsomes. Coadministration of piplartine protected from kanamycin-induced hair cell loss in zebrafish and protected hearing function, outer hair cells, and presynaptic ribbons in a mouse model of kanamycin ototoxicity. Last, we investigated piplartine's mechanism of action by phospho-omics, immunoblotting, immunohistochemistry, and molecular dynamics experiments. We found an up-regulation of AKT1 signaling in the cochleas of mice cotreated with piplartine. Piplartine treatment normalized kanamycin-induced up-regulation of TRPV1 expression and modulated the gating properties of this receptor. Because aminoglycoside entrance to the inner ear is, in part, mediated by TRPV1, these results suggested that by regulating TRPV1 expression, piplartine blocked aminoglycoside's entrance, thereby preventing the long-term deleterious effects of aminoglycoside accumulation in the inner ear compartment.

Exploring the Effects of Intersubunit Interface Mutations on Virus-Like Particle Structure and Stability.

Virus-like particles (VLPs) from bacteriophage MS2 provide a platform to study protein self-assembly and create engineered systems for drug delivery. Here, we aim to understand the impact of intersubunit interface mutations on the local and global structure and function of MS2-based VLPs. In previous work, our lab identified locally supercharged double mutants [T71K/G73R] that concentrate positive charge at capsid pores, enhancing uptake into mammalian cells. To study the effects of particle size on cellular internalization, we combined these double mutants with a single point mutation [S37P] that was previously reported to switch particle geometry from T = 3 to T = 1 icosahedral symmetry. These new variants retained their enhanced cellular uptake activity and could deliver small-molecule drugs with efficacy levels similar to our first-generation capsids. Surprisingly, these engineered triple mutants exhibit increased thermostability and unexpected geometry, producing T = 3 particles instead of the anticipated T = 1 assemblies. Transmission electron microscopy revealed various capsid assembly states, including wild-type (T = 3), T = 1, and rod-like particles, that could be accessed using different combinations of these point mutations. Molecular dynamics experiments recapitulated the structural rationale in silico for the single point mutation [S37P] forming a T = 1 virus-like particle and showed that this assembly state was not favored when combined with mutations that favor rod-like architectures. Through this work, we investigated how interdimer interface dynamics influence VLP size and morphology and how these properties affect particle function in applications such as drug delivery.

In Silico Exploration of Isoxazole Derivatives of Usnic Acid: Novel Therapeutic Prospects Against α-Amylase for Diabetes Treatment.

Diabetes mellitus (DM) a metabolic disorder characterized by high blood sugar levels causing damage to various organs over time. Current anti-diabetic drugs have limitations and side effects, prompting a search for new inhibitors targeting the α-amylase enzyme. This study aims to discover such inhibitors from thirty isoxazole derivatives of usnic acid using in silico approaches. The potential inhibitory effects of compounds were investigated using ADMET, molecular docking, molecular dynamic simulation, principal component analysis and density functional theory studies. ADMET analysis exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities with no significant side effects which were then investigated using molecular docking experiment to determine the lead compound with the best binding affinity for the α-amylase enzyme. All compounds showed good binding affinity against α-amylase enzyme (-7.9 to -9.2 kcal/mol) where compound-13 showed the best binding affinity of -9.2 kcal/mol forming hydrogen bonds with Leu162, Tyr62, Glu233 and Asp300 amino acids. Furthermore, the binding posture and the stability of the compound-13-α-amylase enzyme complex was confirmed by molecular dynamic simulation experiment. Moreover, compound-13 showed binding energy value of -27.92 ± 5.61 kcal/mol, which indicated it could be an α-amylase inhibitor. Additionally, the reactivity of compound-13 was further confirmed by density functional theory analysis. The above findings suggest compound-13 to be a potential α-amylase inhibitor in DM. And setting the stage for further in vitro and in vivo experimental validation.

Mts1 (S100A4) and Its Peptide Demonstrate Cytotoxic Activity in Complex with Tag7 (PGLYRP1) Peptide.

Receptors of cytokines are major regulators of the immune response. In this work, we have discovered two new ligands that can activate the TNFR1 (tumor necrosis factor receptor 1) receptor. Earlier, we found that the peptide of the Tag (PGLYRP1) protein designated 17.1 can interact with the TNFR1 receptor. Here, we have found that the Mts1 (S100A4) protein interacts with this peptide with a high affinity (Kd = 1.28 × 10-8 M), and that this complex is cytotoxic to cancer cells that have the TNFR1 receptor on their surface. This complex induces both apoptosis and necroptosis in cancer cells with the involvement of mitochondria and lysosomes in cell death signal transduction. Moreover, we have succeeded in locating the Mts1 fragment that is responsible for protein-peptide interaction, which highly specifically interacts with the Tag7 protein (Kd = 2.96 nM). The isolated Mts1 peptide M7 also forms a complex with 17.1, and this peptide-peptide complex also induces the TNFR1 receptor-dependent cell death. Molecular docking and molecular dynamics experiments show the amino acids involved in peptide binding and that may be used for peptidomimetics' development. Thus, two new cytotoxic complexes were created that were able to induce the death of tumor cells via the TNFR1 receptor. These results may be used in therapy for both cancer and autoimmune diseases.

Mechanism of Action of Curcumin for Rheumatoid Arthritis Based on Machine Learning, Molecular Dynamics and Cellular Experiments

<i>Objective</i>: Curcumin has been widely used in rheumatoid arthritis (RA) treatment and the previous study also proved its effectiveness. However, the pharmacological mechanism is still not clear. The current study intends to discuss the potential mechanism of action of curcumin in RA treatment through machine learning, network pharmacology, molecular dynamics and cellular experiments.<i>Methods</i>: RA-related microarray data were obtained from three GEO datasets: GSE55235, GSE55457 and GSE77298. Machine learning methods including XGBOOST, LASSO and SVM were adopted to screen out potential targets of RA pathogenesis. Online tools SwissTargetPrediction and Similarity ensemble approach were visited to predict potential targets of action of curcumin. The key target was identified via a Venn diagram and processed for molecular docking and molecular dynamics simulation with curcumin. Fibroblast-like synoviocytes (RA-FLSs) were selected to study the effect of curcumin at different concentrations (20, 40 and 80 μmol/L) on cell proliferation and apoptosis using MTT and flow cytometry assays. In addition, Western blot was used to examine the protein level.<i>Results</i>: Arachidonate 5-Lipoxygenase (ALOX5) was identified as a key target of RA following bioinformatics prediction. Results of molecular docking and molecular dynamics simulation demonstrated the tight binding between curcumin and ALOX5 with stable function. RA-FLSs intervened with different concentrations of curcumin (20, 40 and 80 mol/L) exhibited decreased potential in proliferation while increased apoptosis, which were in a dose-dependent manner. Additionally, with the increase of curcumin concentration, the protein level of ALOX5 gradually decreased. <i>Conclusion</i>: Curcumin may exert its therapeutic effects in RA treatment via down-regulating the expression of ALOX5.

Structural Determinants of Peptide Nanopore Formation.

We have evolved the nanopore-forming macrolittin peptides from the bee venom peptide melittin using successive generations of synthetic molecular evolution. Despite their sequence similarity to the broadly membrane permeabilizing cytolytic melittin, the macrolittins have potent membrane selectivity. They form nanopores in synthetic bilayers made from 1-palmitoyl, 2-oleoyl-phosphatidylcholine (POPC) at extremely low peptide concentrations and yet have essentially no cytolytic activity against any cell membrane, even at high concentration. Here, we explore the structural determinants of macrolittin nanopore stability in POPC bilayers using atomistic molecular dynamics simulations and experiments on macrolittins and single-site variants. Simulations of macrolittin nanopores in POPC bilayers show that they are stabilized by an extensive, cooperative hydrogen bond network comprised of the many charged and polar side chains interacting with each other via bridges of water molecules and lipid headgroups. Lipid molecules with unusual conformations participate in the H-bond network and are an integral part of the nanopore structure. To explore the role of this H-bond network on membrane selectivity, we swapped three critical polar residues with the nonpolar residues found in melittin. All variants have potency, membrane selectivity, and cytotoxicity that were intermediate between a cytotoxic melittin variant called MelP5 and the macrolittins. Simulations showed that the variants had less organized H-bond networks of waters and lipids with unusual structures. The membrane-spanning, cooperative H-bond network is a critical determinant of macrolittin nanopore stability and membrane selectivity. The results described here will help guide the future design and optimization of peptide nanopore-based applications.

Trichodelphinine A alleviates pulmonary fibrosis by inhibiting collagen synthesis via NOX4-ARG1/TGF-β signaling pathway

BackgroundPulmonary fibrosis, a progressive and fatal lung disease with no effective treatment medication, is characterized by lung remodeling and fibroblastic foci caused by an oxidative imbalance with an overloading deposition of collagen. Trichodelphinine A, a hetisine-type C20-diterpenoid alkaloid, was found anti-fibrotic activity in vitro, but its effect and mechanism on pulmonary fibrosis still unknown. PurposeOur study aimed to investigate and validate the anti-fibrotic properties of trichodelphinine A in pulmonary fibrosis animals induced by bleomycin (BLM), and its mechanism whether via NOX4-ARG1/TGF-β signaling pathway. MethodsThe anti-fibrotic effects of trichodelphinine A were evaluated using BLM-induced rats through indicators of lung histopathology and collagen synthesis. Dynamic metabolomics evaluated the metabolic disorder and therapeutic effect of trichodelphinine A. The interaction between trichodelphinine A and NOX4 receptor was confirmed using CETSA and molecular dynamics experiments. Molecular biology experiments were conducted in NOX4 gene knockout mice to investigate the intervention effect of trichodelphinine A. ResultsTrichodelphinine A could suppress histopathologic changes, collagen deposition and proinflammatory cytokine release pulmonary fibrosis in bleomycin induced rats. Dynamic metabolomics studies revealed that trichodelphinine A could correct endogenous metabolic disorders of arachidonic acid, arginine and proline during fibrosis development, which revealed that the regulation of oxidative stress and amino acid metabolism targeting NOX4 and ARG1 may be the main pharmacological mechanisms of trichodelphinine A on pulmonary fibrosis. We further determined that trichodelphinine A inhibited over oxidative stress and collagen deposition by suppressing Nrf2-keap1 and ARG1-OAT signaling pathways, respectively. Molecular dynamics studies showed that trichodelphinine A was directly binds with NOX4, in which PHE354 and THR355 residues of NOX4 are critical binding sites for trichodelphinine A. Mechanistic validation in cells or mice with NOX4 knockout or silencing suggested that the anti-fibrotic effects of trichodelphinine A depended on inhibition of NOX4 to suppress ARG1/OAT activation and TGF-β/Smads signaling pathway. ConclusionCollectively, our findings indicate a powerful anti-fibrotic function of trichodelphinine A in pulmonary fibrosis via targeting NOX4. NOX4 mediates the activation of ARG1/OAT to regulate arginase-proline metabolism, and promotes TGF-β/Smads signaling pathway, thereby affecting the collagen synthesis in pulmonary fibrosis, which is a novel finding and indicates that inhibition of NOX4 is a novel therapeutic strategy for pulmonary fibrosis.

Runaway transition in irreversible polymer condensation with cyclization

The process of polymer condensation, i.e., the formation of bonds between reactive end groups, is ubiquitous in both industry and biology. Here we study generic systems undergoing polymer condensation in competition with cyclization. Using a generalized Smoluchowski theory, molecular dynamics simulations and experiments with DNA and ATP-consuming T4 ligase, we find that this system displays a transition, from a ring-dominated regime with finite-length chains at infinite time to a linear-polymers-dominated one with chains that keep growing in time. Finally, we show that fluids prepared close to the transition may have widely different compositions and rheology at large condensation times. Published by the American Physical Society 2024

Deep potential molecular dynamic and electrochemical experiments to reveal the structure and behavior of Mn(II) in magnesium electrolysis

Deep potential molecular dynamic and electrochemical experiments to reveal the structure and behavior of Mn(II) in magnesium electrolysis

Topological isomerism design of Demulsifiers: A fusion of molecular dynamics simulation and experiment

Demulsifiers are crucial for enhancing crude oil extraction and transportation efficiency by facilitating the separation of oil–water emulsions. However, research conducted on the design and synthesis of demulsifiers based on the results of molecular dynamics simulation remains scarce. Herein, we designed eight block polyethers, and explored their interfacial behaviors at the oil–water interface via molecular dynamics simulation. Correspondingly, eight block polyether demulsifiers were synthesized, and their interface properties were tested. The simulation results were consistent with the experimental results, indicating that the energy of simulation systems could be efficiently reduced by designed molecules, and that the prepared demulsifiers with the same structure could achieve effective demulsification correspondingly. Based on the simulation and experimental results, a “hand-shaped” demulsification mechanism model was proposed. The demulsifiers with hydrophobic “palm” and hydrophilic “fingers” demonstrated a more efficient performance in demulsification. The hydrophobic “palm” was stable in the continuous oil phase, and the hydrophilic “fingers” could attract dispersed water droplets to aggregate, facilitating demulsification. The study also finds that longer hydrophilic “fingers” exert stronger molecular force. Combining molecular dynamics simulation and experiment significantly accelerates the development of new demulsifiers, highlighting the utility of this approach in the research on demulsifiers.

Expression analysis and mapping of Viral—Host Protein interactions of Poxviridae suggests a lead candidate molecule targeting Mpox

BackgroundMonkeypox (Mpox) is an important human pathogen without etiological treatment. A viral-host interactome study may advance our understanding of molecular pathogenesis and lead to the discovery of suitable therapeutic targets.MethodsGEO Expression datasets characterizing mRNA profile changes in different host responses to poxviruses were analyzed for shared pathway identification, and then, the Protein–protein interaction (PPI) maps were built. The viral gene expression datasets of Monkeypox virus (MPXV) and Vaccinia virus (VACV) were used to identify the significant viral genes and further investigated for their binding to the library of targeting molecules.ResultsInfection with MPXV interferes with various cellular pathways, including interleukin and MAPK signaling. While most host differentially expressed genes (DEGs) are predominantly downregulated upon infection, marked enrichments in histone modifiers and immune-related genes were observed. PPI analysis revealed a set of novel virus-specific protein interactions for the genes in the above functional clusters. The viral DEGs exhibited variable expression patterns in three studied cell types: primary human monocytes, primary human fibroblast, and HeLa, resulting in 118 commonly deregulated proteins. Poxvirus proteins C6R derived protein K7 and K7R of MPXV and VACV were prioritized as targets for potential therapeutic interventions based on their histone-regulating and immunosuppressive properties. In the computational docking and Molecular Dynamics (MD) experiments, these proteins were shown to bind the candidate small molecule S3I-201, which was further prioritized for lead development.ResultsMPXV circumvents cellular antiviral defenses by engaging histone modification and immune evasion strategies. C6R-derived protein K7 binding candidate molecule S3I-201 is a priority promising candidate for treating Mpox.

Repurposing of antimycobacterium drugs for COVID-19 treatment by targeting SARS CoV-2 main protease: An in-silico perspective

The global mortality rate has been significantly impacted by the COVID-19 pandemic, caused by the SARS CoV-2 virus. Although the pursuit for a potent antiviral is still in progress, experimental therapies based on repurposing of existing drugs is being attempted. One important therapeutic target for COVID-19 is the main protease (Mpro) that cleaves the viral polyprotein in its replication process. Recently minocycline, an antimycobacterium drug, has been successfully implemented for the treatment of COVID-19 patients. But it’s mode of action is still far from clear. Furthermore, it remains unresolved whether alternative antimycobacterium drugs can effectively regulate SARS CoV-2 by inhibiting the enzymatic activity of Mpro. To comprehend these facets, eight well-established antimycobacterium drugs were put through molecular docking experiments. Four of the antimycobacterium drugs (minocycline, rifampicin, clofazimine and ofloxacin) were selected by comparing their binding affinities towards Mpro. All of the four drugs interacted with both the catalytic residues of Mpro (His41 and Cys145). Additionally, molecular dynamics experiments demonstrated that the Mpro-minocyline complex has enhanced stability, experiences reduced conformational fluctuations and greater compactness than other three Mpro-antimycobacterium and Mpro-N3/lopinavir complexes. This research furnishes evidences for implementation of minocycline against SARS CoV-2. In addition, our findings also indicate other three antimycobacterium/antituberculosis drugs (rifampicin, clofazimine and ofloxacin) could potentially be evaluated for COVID-19 therapy.

Experimental and molecular dynamics simulation based investigation to understand tribological performance of graphene reinforced thermoplastic polyurethane (Gr/TPU) nanocomposites

Ongoing innovative research in tribology aims to develop high-performance polymer nanocomposite (PNC) materials that offer significant improvements in efficiency, reliability, and durability across various engineering systems. Selection of appropriate nanoreinforcements is crucial for maximizing the tribological behavior in PNCs. The primary objective is to investigate how various factors, such as graphene (Gr) loadings, processing techniques, normal loading, and sliding velocity influence the tribological behavior of thermoplastic polyurethane (TPU) and graphene reinforced thermoplastic polyurethane (Gr/TPU) nanocomposites using molecular dynamics (MD) simulation and experiments. Nanocomposite materials fabricated by ultrasonication methods, test specimens are prepared in appropriate dimensions as per ASTM (American Society for Testing and Materials) and DIN (Deutsches Institut für Normung) standard. MD simulations are conducted on the developed plate and rod models under different sliding velocity, pressing and stabbing depth conditions to understand fundamental insights into the friction and wear mechanisms of Gr/TPU nanocomposites at the atomic level. Morphological studies using scanning electron microscopy (SEM) micrographs indicate no case of Gr agglomeration up to 3 wt% Gr/TPU nanocomposite. Energy dispersive spectroscopy (EDS) analysis confirms presence of Carbon (c), Nitrogen (N) and Oxygen (O) in Gr/TPU nanocomposites. Finally the obtained results from MD simulation and experiments show a significant trend of similarity.

Inkjet printing of triethylene glycol monomethyl ether (TEGMME)-based ink droplet on oxygen plasma treated PDMS substrate for flexible circuit

Circuits fabricated by inkjet printing on polydimethylsiloxane (PDMS) substrate is a promising direction of flexible electronics. Oxygen plasma treatment is a commonly used method to modify PDMS from hydrophobic to hydrophilic, which is prerequisite before inkjet printing. In this study, inkjet printing of triethylene glycol monomethyl ether (TEGMME)-based silver dispersion nanoparticle droplets on oxygen plasma treated PDMS was investigated by molecular dynamics simulations and experiments. It is revealed that the improved hydrophilicity of PDMS surface is contributed to the replacement of hydrophilic groups (-OH and -C=O) from hydrophobic groups (-CH3) on the PDMS molecular chains. Considering the existence of hydroxyl groups in TEGMME molecules, more hydrogen bonds are formed at the interface between the treated PDMS and TEGMME-based droplets during printing process. These significantly optimize the merging of droplets and the distribution of silver nanoparticles. Moreover, too short plasma treatment will lead to poor circuit morphology caused by weak hydrophilicity, while too long treatment will lead to defects caused by coffee ring effect. The suggested process parameter is treating PDMS for 30 s at a radio-frequency power of 45 W. The morphology of printed circuit is greatly improved and the resistivity decreased to 2.5 Ω/mm. A PDMS-based pressure sensor is designed and fabricated by the proposed inkjet printing process, which shows a sensitivity of 1.8 Ω/kPa and R2 of 0.98.

Salt damage on asphalt surfaces under repeated dissolution at molecular scale

Salt damage on asphalt surfaces is primarily attributed to migration of ions, with repeated dissolution exacerbating the degradation of asphalt performance. To investigate micro mechanism of salt corrosion on asphalt surfaces during repeated dissolution, this research uses molecular dynamics (MD) simulation and experiments to measure interactions among asphalt, salt, and water. Asphalt-salt systems and asphalt-water interfaces are built to calculate molecular damage behaviors by energies, mobilities, and distributions, along with micro-morphology and rheological properties of asphalt samples under salt corrosion. The interaction energies of salt with asphalt exhibit a hierarchy with Mg2+ ˃ Ca2+ ˃ Na+ and SO42- ˃ Cl-, predominantly governed by electrostatic energies. Repeated dissolution is a dynamic damage process. When water contacts on salt-eroded asphalt surfaces, salt ions migrate into water, forming solutions. Sulfates exhibit slower mobility and higher structural stability compared to chlorides, owing to smaller free volume, stronger interaction, and weaker water debonding. Rheologically, salt-eroded asphalt manifests as stiffer and tougher than water-eroded or base asphalt. These asphalt samples undergo softening and increased viscosity due to loss of salt ions. Consequently, compared to chlorides, sulfates demonstrate stronger interactions with asphalt and more difficulty in diffusing to water, resulting in severer damage on asphalt surfaces.

Molecular-level explanation of interactions of random and block polycarboxylic acid dispersants with bituminous coal in coal–water slurry through experiments and simulations

The adsorption conformations of random-structure polycarboxylic acid (PCR) and block-structure polycarboxylic acid (PCB) on coal surfaces were analyzed from a microscopic perspective. This analysis involved a combination of molecular dynamics (MD) simulations and experiments. The saturation adsorption amount of PCB was found to be significantly much larger than that of PCR. Additionally, observations from the contact angle and X-ray photoelectron spectroscopy confirmed that PCB exhibited superior wetting performance on coal compared to PCR and had a greater adsorption layer thickness. The relative concentration changes and the mean square displacement (MSD) of water indicate that the better adsorption of PCB on the coal surface makes the water molecules more evenly distributed, which improves hydration, increases the thickness of the “adsorption layer”, and enhances the mobility of water molecules. The interaction energy suggests the block structure of PCB is more favorable for molecular extension due to its well-defined structure. This provides a theoretical and experimental basis for expanding the molecular sequence structure design of polycarboxylic acid dispersants.

Molecular dynamics simulations and experimental studies on low-temperature growth of GaN

Growth mechanisms of (0001) wurtzite GaN films at low temperature are investigated by molecular dynamics simulations and experiments. The crystallization properties of GaN films deteriorate dramatically at low temperature due to the limited energy available for atomic surface migration and incorporation into the perfect lattice sites. In our simulation, growth interruption stage is periodically introduced and the as-deposited GaN films are treated with energy-carrying argon ions at this stage. The surface atoms located at the weak binding sites can acquire energy from the argon ions for secondary migration and incorporation into the perfect lattice sites. As a result, the crystallization properties of GaN films are significantly improved. GaN films are experimentally grown on sputtered AlN/sapphire substrates at 600 °C via inductively coupled plasma metal organic chemical vapor deposition along with periodic argon plasma treatment. The as-deposited film acquires energy from the plasma, leading to significant improvement of the crystalline properties. The surface morphology of the GaN film demonstrates a noticeable smoothing effect, with an evident increase in grain size from submicron to micron level. Additionally, GaN film with the optimized surface morphology exhibits high c-axis and in-plane orientations, and the full width half maximums of (002) and (102) x-ray diffraction rocking curves are 0.25° and 0.32°, respectively. These results provide effective guidance for the growth of GaN films at low temperature.

Three-step docking by WIPI2, ATG16L1, and ATG3 delivers LC3 to the phagophore.

The covalent attachment of ubiquitin-like LC3 proteins (microtubule-associated proteins 1A/1B light chain 3) prepares the autophagic membrane for cargo recruitment. We resolve key steps in LC3 lipidation by combining molecular dynamics simulations and experiments in vitro and in cellulo. We show how the E3-like ligaseautophagy-related 12 (ATG12)-ATG5-ATG16L1 in complex with the E2-like conjugase ATG3 docks LC3 onto the membrane in three steps by (i) the phosphatidylinositol 3-phosphate effector protein WD repeat domain phosphoinositide-interacting protein 2 (WIPI2), (ii) helix α2 of ATG16L1, and (iii) a membrane-interacting surface of ATG3. Phosphatidylethanolamine (PE) lipids concentrate in a region around the thioester bond between ATG3 and LC3, highlighting residues with a possible role in the catalytic transfer of LC3 to PE, including two conserved histidines. In a near-complete pathway from the initial membrane recruitment to the LC3 lipidation reaction, the three-step targeting of the ATG12-ATG5-ATG16L1 machinery establishes a high level of regulatory control.

Mechanisms of plastic deformation and mechanical strengthening in nano-scale Ti-Ti2Cu eutectoids: A study combined molecular dynamics simulation and experiment

Ti-Cu eutectoid or near-eutectoid alloys were found to possess exceptional high strength owning to the nano-scale lamellar structure of Ti2Cu and α-Ti after additive manufacturing, they are potential candidates for high-performance materials. To reveal the deformation and strengthening mechanisms, the molecular dynamics (MD) simulations and experimental analysis were carried out upon Ti-Ti2Cu lamellae. In this work, we focused on revealing the interface dislocations (IDs) pattern and its effects on the dynamic evolution of the lattice dislocations (LDs) at the Ti/Ti2Cu interface with (0001)α//(01‾3)Ti2Cu orientation relationship. Atomistic simulations depicted that the equilibrium Ti/Ti2Cu interface contains three groups of partial dislocations which dictate two interfacial coherent structures with low stacking fault energy. Each ID consists of several segments, connected by atomic steps with identical direction. The nucleation sites of LDs under external loading locate at the intersection between the dislocation segment and the atomic step, which is related to the local high atom strain. Under compression deformation, the 〈100〉{011} and 〈331〉{103} slip systems in Ti2Cu, and the 〈112¯3〉{101¯1} slip system in α-Ti are activated, achieving a co-deformation mechanism in the Ti-Ti2Cu multilayers. The dislocation-interface interactions are responsible for the deformation plasticity and in turn governs the mechanical strengthening. During nanoindentation tests, larger hardness (∼6.2 GPa) and smaller activation volume (∼12b3) were found in the Ti-Ti2Cu lamellae, which is mainly ascribed to the presence of high-density lamellae interface and confined layer slip, resulting in interface-mediated dislocation annihilation/deposition and consequent high strain hardening. The MD simulations, nanoindentation tests and TEM investigations of interlayer dislocation activity support the strengthening mechanism of dislocation-interface interactions.

Boundary slip and lubrication mechanisms of organic friction modifiers with effect of surface moisture

Surface moisture or humidity impacting the lubrication property is a ubiquitous phenomenon in tribological systems, which is demonstrated by a combination of molecular dynamics (MD) simulation and experiment for the organic friction modifier (OFM)-containing lubricant. The stearic acid and poly-α-olefin 4cSt (PAO4) were chosen as the OFM and base oil molecules, respectively. The physical adsorption indicates that on the moist surface water molecules are preferentially adsorbed on friction surface, and even make OFM adsorption film thoroughly leave surface and mix with base oil. In shear process, the adsorption of water film and desorption OFM film are further enhanced, particularly under higher shear rate. The simulated friction coefficient (that is proportional to shear rate) increases firstly and then decreases with thickening water film, in good agreement with experiments, while the slip length shows a contrary change. The wear increases with humidity due to tribochemistry revealing the continuous formation and removal of Si-O-Si network. The tribological discrepancy of OFM-containing lubricant in dry and humid conditions is attributed to the slip plane’s transformation from the interface between OFM adsorption film and lubricant bulk to the interface between adsorbed water films. This work provides a new thought to understand the boundary lubrication and failure of lubricant in humid environments, likely water is not always harmful in oil lubrication systems.