Deciphering principles of nucleosome interactions and impact of cancer-associated mutations from comprehensive interaction network analysis.

Nucleosomes represent hubs in chromatin organization and gene regulation and interact with a plethora of chromatin factors through different modes. In addition, alterations in histone proteins such as cancer mutations and post-translational modifications have profound effects on histone/nucleosome interactions. To elucidate the principles of histone interactions and the effects of those alterations, we developed histone interactomes for comprehensive mapping of histone-histone interactions (HHIs), histone-DNA interactions (HDIs), histone-partner interactions (HPIs) and DNA-partner interactions (DPIs) of 37 organisms, which contains a total of 3808 HPIs from 2544 binding proteins and 339 HHIs, 100 HDIs and 142 DPIs across 110 histone variants. With the developed networks, we explored histone interactions at different levels of granularities (protein-, domain- and residue-level) and performed systematic analysis on histone interactions at a large scale. Our analyses have characterized the preferred binding hotspots on both nucleosomal/linker DNA and histone octamer and unraveled diverse binding modes between nucleosome and different classes of binding partners. Last, to understand the impact of histone cancer-associated mutations on histone/nucleosome interactions, we complied one comprehensive cancer mutation dataset including 7940 cancer-associated histone mutations and further mapped those mutations onto 419,125 histone interactions at the residue level. Our quantitative analyses point to histone cancer-associated mutations' strongly disruptive effects on HHIs, HDIs and HPIs. We have further predicted 57 recurrent histone cancer mutations that have large effects on histone/nucleosome interactions and may have driver status in oncogenesis.

A novel approach to study multi-domain motions in JAK1's activation mechanism based on energy landscape.

The family of Janus Kinases (JAKs) associated with the JAK-signal transducers and activators of transcription signaling pathway plays a vital role in the regulation of various cellular processes. The conformational change of JAKs is the fundamental steps for activation, affecting multiple intracellular signaling pathways. However, the transitional process from inactive to active kinase is still a mystery. This study is aimed at investigating the electrostatic properties and transitional states of JAK1 to a fully activation to a catalytically active enzyme. To achieve this goal, structures of the inhibited/activated full-length JAK1 were modelled and the energies of JAK1 with Tyrosine Kinase (TK) domain at different positions were calculated, and Dijkstra's method was applied to find the energetically smoothest path. Through a comparison of the energetically smoothest paths of kinase inactivating P733L and S703I mutations, an evaluation of the reasons why these mutations lead to negative or positive regulation of JAK1 are provided. Our energy analysis suggests that activation of JAK1 is thermodynamically spontaneous, with the inhibition resulting from an energy barrier at the initial steps of activation, specifically the release of the TK domain from the inhibited Four-point-one, Ezrin, Radixin, Moesin-PK cavity. Overall, this work provides insights into the potential pathway for TK translocation and the activation mechanism of JAK1.

Influence Mechanism of Interfacial Oxidation of Li3YCl6 Solid Electrolyte on Reduction Potential.

Halide-based solid electrolytes are promising candidates for all solid-state lithium-ion batteries (ASSLBs) due to their high ionic conductivity, wide electrochemical window, and excellent chemical stability with cathode materials. However, when tested in practice, their intrinsic electrochemical stability windows do not well match the conditions for stable operation of ASSBs. Existing literature reports halide-based ASSBs that still operate well outside the electrochemical stability window, while ASSBs that do not operate within the window are not well studied or the studies are based on the cathode material interface. In this study, we aim to elucidate the mechanism behind all-solid-state battery failure by investigating how the reduction potential of Li3YCl6 solid-state electrolyte itself changes under overcharging conditions. Our findings demonstrate that in Li-In|Li3YCl6|Li3YCl6-C half-cells during the first state of charge, Cl ions participate in charge compensation, resulting in a depletion of ligands. This phenomenon significantly affects the reduction potential of Y3+, causing it to be reduced to Y2Cl3 and ultimately to Y0 at conditions far exceeding its actual reduction potential. Furthermore, we analyze the interfacial impedance induced by this process and propose a novel perspective on battery failure.

Bound ion effects: Using machine learning method to study the kinesin Ncd's binding with microtubule.

Drosophila Ncd proteins are motor proteins that play important roles in spindle organization. Ncd and the tubulin dimer are highly charged. Thus, it is crucial to investigate Ncd-tubulin dimer interactions in the presence of ions, especially ions that are bound or restricted at the Ncd-tubulin dimer binding interfaces. To consider the ion effects, widely used implicit solvent models treat ions implicitly in the continuous solvent environment without focusing on the individual ions' effects. But highly charged biomolecules such as the Ncd and tubulin dimer may capture some ions at highly charged regions as bound ions. Such bound ions are restricted to their binding sites; thus, they can be treated as part of the biomolecules. By applying multiscale computational methods, including the machine-learning-based Hybridizing Ions Treatment-2 program, molecular dynamics simulations, DelPhi, and DelPhiForce, we studied the interaction between the Ncd motor domain and the tubulin dimer using a hybrid solvent model, which considers the bound ions explicitly and the other ions implicitly in the solvent environment. To identify the importance of treating bound ions explicitly, we also performed calculations using the implicit solvent model without considering the individual bound ions. We found that the calculations of the electrostatic features differ significantly between those of the hybrid solvent model and the pure implicit solvent model. The analyses show that treating bound ions at highly charged regions explicitly is crucial for electrostatic calculations. This work proposes a machine-learning-based approach to handle the bound ions using the hybrid solvent model. Such an approach is not only capable of handling kinesin-tubulin complexes but is also appropriate for other highly charged biomolecules, such as DNA/RNA, viral capsid proteins, etc.

JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation.

Janus tyrosine kinase 3 (JAK3) is primarily expressed in immune cells and is needed for signaling by the common gamma chain (γc) family of cytokines. Abnormal JAK3 signal transduction can manifest as hematological disorders, e.g., leukemia, severe combined immunodeficiency (SCID) and autoimmune disease states. While regulatory JAK3 phosphosites have been well studied, here a functional proteomics approach coupling a JAK3 autokinase assay to mass spectrometry revealed ten previously unreported autophosphorylation sites (Y105, Y190, Y238, Y399, Y633, Y637, Y738, Y762, Y824, and Y841). Of interest, Y841 was determined to be evolutionarily conserved across multiple species and JAK family members, suggesting a broader role for this residue. Phospho-substitution mutants confirmed that Y841 is also required for STAT5 tyrosine phosphorylation. The homologous JAK1 residue Y894 elicited a similar response to mutagenesis, indicating the shared importance for this site in JAK family members. Phospho-specific Y841-JAK3 antibodies recognized activated kinase from various T-cell lines and transforming JAK3 mutants. Computational biophysics analysis linked Y841 phosphorylation to enhanced JAK3 JH1 domain stability across pH environments, as well as to facilitated complementary electrostatic JH1 dimer formation. Interestingly, Y841 is not limited to tyrosine kinases, suggesting it represents a conserved ubiquitous enzymatic function that may hold therapeutic potential across multiple kinase families.

Pressure-induced phase transitions and superconductivity in a quasi-1-dimensional topological crystalline insulator α-Bi4Br4.

Great progress has been achieved in the research field of topological states of matter during the past decade. Recently, a quasi-1-dimensional bismuth bromide, Bi4Br4, has been predicted to be a rotational symmetry-protected topological crystalline insulator; it would also exhibit more exotic topological properties under pressure. Here, we report a thorough study of phase transitions and superconductivity in a quasihydrostatically pressurized α-Bi4Br4 crystal by performing detailed measurements of electrical resistance, alternating current magnetic susceptibility, and in situ high-pressure single-crystal X-ray diffraction together with first principles calculations. We find a pressure-induced insulator-metal transition between ∼3.0 and 3.8 GPa where valence and conduction bands cross the Fermi level to form a set of small pockets of holes and electrons. With further increase of pressure, 2 superconductive transitions emerge. One shows a sharp resistance drop to 0 near 6.8 K at 3.8 GPa; the transition temperature gradually lowers with increasing pressure and completely vanishes above 12.0 GPa. Another transition sets in around 9.0 K at 5.5 GPa and persists up to the highest pressure of 45.0 GPa studied in this work. Intriguingly, we find that the first superconducting phase might coexist with a nontrivial rotational symmetry-protected topology in the pressure range of ∼3.8 to 4.3 GPa; the second one is associated with a structural phase transition from monoclinic C2/m to triclinic P-1 symmetry.

Fabrication of Hollow CoP/TiOx Heterostructures for Enhanced Oxygen Evolution Reaction.

Transition-metal phosphides have flourished as promising candidates for oxygen evolution reaction (OER) electrocatalysts. Herein, it is demonstrated that the electrocatalytic OER performance of CoP can be greatly improved by constructing a hybrid CoP/TiOx heterostructure. The CoP/TiOx heterostructure is fabricated using metal-organic framework nanocrystals as templates, which leads to unique hollow structures and uniformly distributed CoP nanoparticles on TiOx . The strong interactions between CoP and TiOx in the CoP/TiOx heterostructure and the conductive nature of TiOx with Ti3+ sites endow the CoP-TiOx hybrid material with high OER activity comparable to the state-of-the-art IrO2 or RuO2 OER electrocatalysts. In combination with theoretical calculations, this work reveals that the formation of CoP/TiOx heterostructure can generate a pathway for facile electron transport and optimize the water adsorption energy, thus promoting the OER electrocatalysis.

Electrochemical nitrogen fixation and utilization: theories, advanced catalyst materials and system design.

Nitrogen is a fundamental constituent for all living creatures on the Earth and modern industrial society. The current nitrogen industry is largely powered by fossil fuels with huge energy consumption and carbon dioxide emission, and nitrogen pollution in surface water bodies induced by the indiscriminate discharge of industrial and domestic wastewater has become a worldwide environmental concern. Electrochemical techniques for nitrogen fixation and transformation under mild conditions are promising approaches to meet the challenge of efficiently managing and balancing the nitrogen cycle, where the rational design of advanced electrocatalysts from both structural and compositional aspects down to the nanoscale plays the most essential role. Herein, important nitrogen species including dinitrogen (N2), ammonia (NH3) and hydrazine (N2H4), their transformation processes between each other including the nitrogen reduction reaction (NRR), ammonia oxidation reaction (AOR) and hydrazine oxidation reaction (HzOR), and research progress on the development of related electrocatalysts are systematically summarized, aiming at establishing a general picture of the whole nitrogen cycle instead of a certain single reaction. Strategies combining theoretical computations and experimental optimizations are proposed to improve the catalytic performance including activity, efficiency, selectivity and stability, finally contributing to a self-sufficient and carbon-free "green" nitrogen economy.

Revealing the mechanism of SARS-CoV-2 spike protein binding with ACE2.

A large population in the world has been infected by COVID-19. Understanding the mechanisms of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is important for management and treatment of the COVID-19. When it comes to the infection process, one of the most important proteins in SARS-CoV-2 is the spike (S) protein, which is able to bind to human Angiotensin-Converting Enzyme 2 (ACE2) and initializes the entry of the host cell. In this study, we implemented multi-scale computational approaches to study the electrostatic features of the interfaces of the SARS-CoV-2 S protein Receptor Binding Domain (RBD) and ACE2. The simulations and analyses were performed on high-performance computing resources in Texas Advanced Computing Center (TACC). Our study identified key residues on the SARS-CoV-2, which can be used as targets for future drug design. The results shed lights on future drug design and therapeutic targets for COVID-19.

Antiperovskite Intermetallic Nanoparticles for Enhanced Oxygen Reduction.

Antiperovskite Co3 InC0.7 N0.3 nanomaterials with highly enhanced oxygen reduction reaction (ORR) performance were prepared by tuning nitrogen contents through a metal-organic framework (MOF)-derived strategy. The nanomaterial surpasses all reported noble-metal-free antiperovskites and even most perovskites in terms of onset potential (0.957 V at J=0.1 mA cm-2 ) and half-wave potential (0.854 V). The OER and zinc-air battery performance demonstrate its multifunctional oxygen catalytic activities. DFT calculation was performed and for the first time, a 4 e- dissociative ORR pathway on (200) facets of antiperovskite was revealed. Free energy studies showed that nitrogen substitution could strengthen the OH desorption as well as hydrogenation that accounts for the enhanced ORR performance. This work expands the scope for material design via tailoring the nitrogen contents for optimal reaction free energy and hence performance of the antiperovskite system.

Fe2 N/S/N Codecorated Hierarchical Porous Carbon Nanosheets for Trifunctional Electrocatalysis.

Construction of multifunctional highly active earth-abundant electrocatalysts on a large scale is a great challenge due to poor control over nanostructural features and limited active sites. Here, a simple methodology to tailor metal-organic frameworks (MOFs) to extract highly active multifunctional electrocatalysts on a large scale for oxygen reduction (ORR), oxygen evolution (OER), and hydrogen evolution reaction (HER) is presented. The N, S codoped Fe2 N decorated highly porous and defect-rich carbon nanosheets are grown using MOF xerogels, melamine, and polyvinylpyrollidone. The resulting catalyst exhibits excellent activity for ORR with an onset (0.92 V) and half-wave (0.81 V) potential similar to state-of-the-art Pt/C catalysts. The catalyst also shows outstanding OER and HER activities with a small overpotential of 360 mV in 1 m KOH and -123 mV in 0.5 m H2 SO4 at a current density of 10 mA cm-2 , respectively. Excellent catalytic properties are further supported by theoretical calculations where relevant models are built and various possible activation sites are identified by first-principles calculations. The results suggest that the carbon atoms adjacent to heteroatoms as well as Fe2 -N sites present the active sites for improved catalytic response, which is in agreement with the experimental results.

High-Performance Energy Storage and Conversion Materials Derived from a Single Metal-Organic Framework/Graphene Aerogel Composite.

Metal oxides and carbon-based materials are the most promising electrode materials for a wide range of low-cost and highly efficient energy storage and conversion devices. Creating unique nanostructures of metal oxides and carbon materials is imperative to the development of a new generation of electrodes with high energy and power density. Here we report our findings in the development of a novel graphene aerogel assisted method for preparation of metal oxide nanoparticles (NPs) derived from bulk MOFs (Co-based MOF, Co(mIM)2 (mIM = 2-methylimidazole). The presence of cobalt oxide (CoOx) hollow NPs with a uniform size of 35 nm monodispersed in N-doped graphene aerogels (NG-A) was confirmed by microscopic analyses. The evolved structure (denoted as CoOx/NG-A) served as a robust Pt-free electrocatalyst with excellent activity for the oxygen reduction reaction (ORR) in an alkaline electrolyte solution. In addition, when Co was removed, the resulting nitrogen-rich porous carbon-graphene composite electrode (denoted as C/NG-A) displayed exceptional capacitance and rate capability in a supercapacitor. Further, this method is readily applicable to creation of functional metal oxide hollow nanoparticles on the surface of other carbon materials such as graphene and carbon nanotubes, providing a good opportunity to tune their physical or chemical activities.

Kinetic-Controlled Formation of Bimetallic Metal-Organic Framework Hybrid Structures.

Heterometallic metal-organic frameworks (MOFs) are constructed from two or more kinds of metal ions, while still remaining their original topologies. Due to distinct reaction kinetics during MOF formation, partial distribution of different metals within a single MOF crystal can lead to sophisticated heterogeneous nanostructures. Here, this study reports an investigation of reaction kinetics for different metal ions in a bimetallic MOF system, the ZIF-8/67 (M(2-mIM)2 , M = Zn for ZIF-8, and Co for ZIF-67, 2-mIM = 2-methylimidazole), by in situ optical method. Distinct kinetics of the two metals forming single-component MOFs are revealed, and when both Co and Zn ions are present in the starting solution, homogeneous distributions of the two metals are only achieved at high Co/Zn ratio, while at low Co/Zn ratio concentration gradient from Co-rich cores to Zn-rich shells is observed. Further, by adding the two metals in sequence, more sophisticated structures are achieved. Specifically, when Co2+ is added first, ZIF-67@ZIF-8/67 core-shell nanocrystals are achieved with tunable core/shell thickness ratio depending on the time intervals; while when Zn2+ is added first, only agglomerates of irregular shape form due to the weak nucleation ability of Zn2+ .

Tensor network methods for extracting conformal field theory data from fixed-point tensors and defect coarse graining.

We present a comprehensive study on extracting conformal field theory data using tensor network methods, especially, from the fixed-point tensor of the linearized tensor renormalization group (lTRG) for the classical two-dimensional Ising model near the critical temperature. Utilizing two different methods, we extract operator scaling dimensions and operator product expansion coefficients by introducing defects on the lattice and by employing the fixed-point tensor. We also explore the effects of pointlike defects in the lattice on the coarse-graining process. We find that there is a correspondence between coarse-grained defect tensors and conformal states obtained from the lTRG fixed-point equation. We also analyze the capabilities and limitations of our proposed coarse-graining scheme for tensor networks with pointlike defects, including graph-independent local truncation (GILT) and higher-order tensor renormalization group (HOTRG). Our results provide a better understanding of the capacity and limitations of the tensor renormalization group scheme in coarse-graining defect tensors, and we show that GILT+HOTRG can be used to give accurate two- and four-point functions under specific conditions. We also find that employing the minimal canonical form further improves the stability of the RG flow.

Serious Mental Illness in Assisted Living Communities: Association with Nursing Home Placement.

OBJECTIVES: Assess prevalence of serious mental illness (SMI) alone, and co-occurring with Alzheimer disease and related dementias (ADRD), among Medicare beneficiaries in assisted living (AL). Examine the association between permanent nursing home (NH) placement and SMI, among residents with and without ADRD. DESIGN: 2018-2019 retrospective cohort of Medicare beneficiaries in AL. Residents were followed for up to 2 years to track their NH placement. We used data from the Medicare Enrollment Database, the Medicare Beneficiary Summary File, Minimum Data Set, and a national directory of state-licensed AL communities. AL residents were identified using a validated, previously reported 9-digit zip code methodology. SETTING AND PARTICIPANTS: A cross-sectional study sample included 289,350 Medicare beneficiaries in 17,265 AL communities across 50 states and in the District of Columbia. METHODS: The outcome was permanent NH placement: a continuous stay for more than 90 days. Key independent variable was presence of SMI-schizophrenia, bipolar disorder, and major depression. Other covariates included sociodemographic factors and presence of other chronic conditions, including ADRD. A linear probability model with robust SEs, and AL-level random effects, was used to test the association between SMI diagnoses, ADRD, and their interactions on NH placement. RESULTS: More than half (55.65%) of AL residents had a diagnosis of SMI, among them 93.2% had major depression, 28.5% schizophrenia, and 22.2% bipolar disorder. Individuals with schizophrenia and bipolar disorder had a significantly lower probability of NH placement, a 32% and a 15% decrease relative to the cohort mean, respectively. Placement risk was significantly greater for residents with ADRD compared to those without, increasing for those who also had schizophrenia or bipolar disorder, 12.9% and 1.5% relative to the sample mean, respectively. CONCLUSION AND IMPLICATIONS: Presence of schizophrenia and bipolar disorder, in conjunction with ADRD, significantly increases the risk of long-term NH placement, suggesting that ALs may not be well prepared to care for these residents.

Hospice providers serving assisted living residents: Association of higher volume with lower quality.

BACKGROUND: Assisted living (AL) community caregivers are known to report lower quality of hospice care. However, little is known about hospice providers serving AL residents and factors that may contribute to, and explain, differences in quality. We examined the association between hospice providers' AL patient-day volume and their quality ratings based on Hospice Item Set (HIS) and Consumer Assessment of Healthcare Providers and Systems (CAHPS) Hospice Surveys. METHODS: This cross-sectional study employed information from the Medicare Compare website and Medicare claims data. Medicare-eligible AL residents were identified using previously validated methods and merged with hospice claims. Linear probability models adjusting for county fixed effects were used to examine the association between hospice provider AL volume, measured as the share of annual hospice patient days from AL residents, and quality measures obtained from HIS and CAHPS. Models controlled for hospice providers' profit status and daily patient census. RESULTS: Higher AL-volume hospice providers were 7 percentage points more likely to have caregivers reporting lower median scores on domains of pain assessment, dyspnea treatment, and emotional support. Their caregivers also reported lower scores in team communications and training family to provide care. Higher AL-volume hospice providers also were 5 percentage points less likely to get higher aggregated scores from all CAHPS domains and 7 percentage points less likely to have higher HIS composite scores. CONCLUSIONS: Hospice providers serving higher volumes of AL patient days had lower quality scores. In order to identify targeted opportunities for quality improvement, research is needed to understand why lower quality providers are concentrated in the AL market.

How does the ion concentration affect the functions of kinesin BimC.

BimC family proteins are bipolar motor proteins belonging to the kinesin superfamily which promote mitosis by crosslinking and sliding apart antiparallel microtubules. Understanding the binding mechanism between the kinesin and the microtubule is crucial for researchers to make advances in the treatment of cancer and other malignancies. Experimental research has shown that the ion concentration affects the function of BimC significantly. But the insights of the ion-dependent function of BimC remain unclear. By combining molecular dynamics (MD) simulations with a series of computational approaches, we studied the electrostatic interactions at the binding interfaces of BimC and the microtubule under different KCl concentrations. We found the electrostatic interaction between BimC and microtubule is stronger at 0 mM KCl compared to 150 mM KCl, which is consistent with experimental conclusions. Furthermore, important salt bridges and residues at the binding interfaces of the complex were identified, which illustrates the details of the BimC-microtubule interactions. Molecular dynamics analyses of salt bridges identified that the important residues on the binding interface of BimC are positively charged, while those residues on the binding interface of the tubulin heterodimer are negatively charged. The finding in this work reveals some important mechanisms of kinesin-microtubule binding, which helps the future drug design for cancer therapy.

Confinement Engineering of Zinc Single-Atom Triggered Charge Redistribution on Ruthenium Site for Alkaline Hydrogen Production.

Optimizing the interaction between metal and support in the supported metal catalysts effectively refines the electronic structure and boosts the catalytic properties of loaded active components. Herein a method is introduced to confine ultrafine ruthenium (Ru) nanoparticles within atomically dispersed Zn-N4 sites on a N-doped carbon network (Ru/Zn-N-C) through the strong electronic metal-support interaction, achieving superior catalytic activity and stability for alkaline hydrogen evolution. Spectroscopic data and theoretical modeling elucidate that the remarkable catalytic performance of Ru sites stems from their strong electronic coupling with neighboring Zn-N4 moiety and pyridinic N/pyrrolic N. This interaction induces an electron-deficient state of Ru, thereby accelerating the dissociation of H2 O and lowering the energy barriers for the desorption of OH* and H*. This insight provides a deeper understanding of the catalytic mechanisms at play. Furthermore, alkaline water electrolyzer using this catalyst as cathode delivers a mass activity of 3 A mgcat -1 at 2.0 V, much surpassing Ru-C. This research opens a novel pathway for the development of advanced materials , tailored for energy storage and conversion applications.

Synergistic action and mechanism of scoparone, a key bioactive component of Artemisia capillaris, and spirodiclofen against spider mites.

BACKGROUND: Plants have numerous defensive secondary metabolites to withstand insect attacks. Scoparone, which is extracted from the medicinal plant Artemisia capillaris, has potent acaricidal effects on Tetranychus cinnabarinus. Spirodiclofen, derived from a tetronic acid derivative, is a potent commercial acaricide that is extensively used globally. However, whether scoparone has synergistic effects when used in conjunction with spirodiclofen and the underlying synergistic mechanism remains unclear. RESULTS: Scoparone exhibited a potent synergistic effect when it was combined with spirodiclofen at a 1:9 ratio. Subsequently, cytochrome P450 monooxygenase (P450) activity, RNA-Seq and qPCR assays indicated that the enzyme activity of P450 and the expression of one P450 gene from T. cinnabarinus, TcCYP388A1, were significantly inhibited by scoparone and spirodiclofen + scoparone; conversely, P450 was activated in spirodiclofen-exposed mites. Importantly, RNAi-mediated silencing of the TcCYP388A1 gene markedly increased the susceptibility of spider mites to spirodiclofen, scoparone and spirodiclofen + scoparone, and in vitro, the recombinant TcCYP388A1 protein could metabolize spirodiclofen. Molecular docking and functional analyses further indicated that R117, which is highly conserved in Arachnoidea species, may be a vital specific binding site for scoparone in the mite TcCYP388A1 protein. This binding site was subsequently confirmed using mutagenesis data, which revealed that this binding site was the sole site selected by scoparone in spider mites over mammalian or fly CYP388A1. CONCLUSIONS: These results indicate that the synergistic effects of scoparone and spirodiclofen on mites occurs through the inhibition of P450 activity, thus reducing spirodiclofen metabolism. The synergistic effect of this potent natural product on the detoxification enzyme-targeted activity of commercial acaricides may offer a sustainable strategy for pest mite resistance management. © 2024 Society of Chemical Industry.

A Comprehensive Study on the Electrostatic Properties of Tubulin-Tubulin Complexes in Microtubules.

Microtubules are key players in several stages of the cell cycle and are also involved in the transportation of cellular organelles. Microtubules are polymerized by α/ß tubulin dimers with a highly dynamic feature, especially at the plus ends of the microtubules. Therefore, understanding the interactions among tubulins is crucial for characterizing microtubule dynamics. Studying microtubule dynamics can help researchers make advances in the treatment of neurodegenerative diseases and cancer. In this study, we utilize a series of computational approaches to study the electrostatic interactions at the binding interfaces of tubulin monomers. Our study revealed that among all the four types of tubulin-tubulin binding modes, the electrostatic attractive interactions in the α/ß tubulin binding are the strongest while the interactions of α/α tubulin binding in the longitudinal direction are the weakest. Our calculations explained that due to the electrostatic interactions, the tubulins always preferred to form α/ß tubulin dimers. The interactions between two protofilaments are the weakest. Thus, the protofilaments are easily separated from each other. Furthermore, the important residues involved in the salt bridges at the binding interfaces of the tubulins are identified, which illustrates the details of the interactions in the microtubule. This study elucidates some mechanistic details of microtubule dynamics and also identifies important residues at the binding interfaces as potential drug targets for the inhibition of cancer cells.