ACS Publications最新文献

{"title":"How Binding Site Flexibility Promotes RNA Scanning by TbRGG2 RRM: A Molecular Dynamics Simulation Study.","authors":"Toon Lemmens, Jiří Šponer, Miroslav Krepl","doi":"10.1021/acs.jcim.4c01954","DOIUrl":"10.1021/acs.jcim.4c01954","url":null,"abstract":"<p><p>RNA recognition motifs (RRMs) are a key class of proteins that primarily bind single-stranded RNAs. In this study, we applied standard atomistic molecular dynamics simulations to obtain insights into the intricate binding dynamics between uridine-rich RNAs and TbRGG2 RRM using the recently developed OL3-Stafix AMBER force field, which improves the description of single-stranded RNA molecules. Complementing structural experiments that unveil a primary binding mode with a single uridine bound, our simulations uncover two supplementary binding modes in which adjacent nucleotides encroach upon the binding pocket. This leads to a unique molecular mechanism through which the TbRGG2 RRM is capable of rapidly transitioning the U-rich sequence. In contrast, the presence of non-native cytidines induces stalling and destabilization of the complex. By leveraging extensive equilibrium dynamics and a large variety of binding states, TbRGG2 RRM effectively expedites diffusion along the RNA substrate while ensuring robust selectivity for U-rich sequences despite featuring a solitary binding pocket. We further substantiate our description of the complex dynamics by simulating the fully spontaneous association process of U-rich sequences to the TbRGG2 RRM. Our study highlights the critical role of dynamics and auxiliary binding states in interface dynamics employed by RNA-binding proteins, which is not readily apparent in traditional structural studies but could represent a general type of binding strategy employed by many RNA-binding proteins.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":"896-907"},"PeriodicalIF":5.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Activity Relationship of Ciprofloxacin towards S-Spike Protein of SARS-CoV-2: Synthesis and <i>In-Silico</i> Evaluation.","authors":"Sahil Kumar, Papiya Dey, Arup Kumar Pathak, Amey Wadawale, Dharmendra K Maurya, Kalyani Natu, Kakoli Bose, Dibakar Goswami","doi":"10.1021/acs.jcim.4c00918","DOIUrl":"10.1021/acs.jcim.4c00918","url":null,"abstract":"<p><p>The recent outbreak of the coronavirus (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has posed serious threats to global health systems. Although several directions have been put by the WHO for effective treatment, use of antibiotics, particularly ciprofloxacin, in suspected and acquired Covid-19 patients has raised an even more serious concern of antibiotic resistance. Ciprofloxacin has been reported to inhibit entry of SARS-CoV-2 into the host cells via interacting with the spike (S) protein. However, a proper structure-activity relationship study of ciprofloxacin with the S-protein is lacking, which inhibits researchers from developing a more potent fluoroquinolone analogue, specific for inhibition of SARS-CoV-2 viral entry. Herein, in order to have a structure-activity relationship study, we have accomplished a short and convergent synthesis of different derivatives of ciprofloxacin and a detailed <i>in-silico</i> study using molecular docking to explore the interactions of the derivatives with S-protein. The ADMET studies also indicated the drug likeliness and nontoxicity of the derivatives. Furthermore, the molecular dynamics simulation approach was used to study the dynamical behavior after the best docked derivative binds to the protein, and the MM-PBSA approach was adopted to calculate the binding energies. This has led to a derivative that has higher interactions with the S-protein compared to ciprofloxacin, without hampering the dynamics of the interactions. The strong affinity of compound <b>5</b> with the SARS-CoV-2 spike RBD protein was further evaluated experimentally using biolayer interferometry (BLI). Furthermore, molecular docking and molecular dynamics simulation were extended to evaluate its binding with the mutated variants Delta and Omicron. We anticipate that the current study could lead to an alternative therapeutic viral inhibitor with a better efficacy than ciprofloxacin.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":"825-844"},"PeriodicalIF":5.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attosecond Rescattering of Laser-Assisted Electron-Proton Collision in Coulomb Potential.","authors":"Mohammad Noh Daud","doi":"10.1021/acs.jpca.4c07219","DOIUrl":"https://doi.org/10.1021/acs.jpca.4c07219","url":null,"abstract":"<p><p>This study investigates the motion of an electron in a Coulomb potential driven by an intense linearly polarized XUV laser pulse analyzed using Gordon-Volkov wave functions. The wave function is decomposed into spherical partial waves to model the scattered electron wave packet after the recollision with a proton. This interaction triggers high harmonic generation, producing coherent X-ray pulses with frequencies that are integer multiples of the XUV field. The research presents a novel method for achieving atomic-scale resolution at nanometer and subfemtosecond levels, enabling observation of electron-proton collisions on an attosecond time scale. It emphasizes the coupling of fields that create resonances in the scattered electron through photon energy exchange with XUV and X-ray pulses, leading to the formation of a Rydberg electron with energy levels up to <i>n</i> = 27 and angular momentum components <i>l</i> = 13 and <i>m</i> = ± 1. The combination of XUV and high-frequency X-ray fields introduces new nonperturbative nonlinear phenomena characterized by differential cross sections derived using the Floquet-Lippmann-Schwinger equation in the first-order Born approximation. The analysis shows that backward-forward scattering involves XUV-electron energy exchange, with peak intensity along the laser polarization vector, while sideways scattering, dominated by X-ray-electron interaction, peaks perpendicular to the polarization. Additionally, the laser-assisted scattering process results in temporary electron capture in a dressed proton-bound state, followed by escape and ejection, with the free electron ponderomotive energy exceeding 10<i>U</i>_<i>p</i>.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Dynamics Insights into Water Transport Mechanisms in Polyamide Membranes: Influence of Cross-Linking Degree.","authors":"Chi Zhang, Guangle Bu, Lida Meng, Dan Lu, Sirui Tong, Zhikan Yao, Danjun Zheng, Lin Zhang","doi":"10.1021/acs.jpcb.4c06566","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c06566","url":null,"abstract":"<p><p>Polyamide (PA) membranes are widely utilized in desalination and water treatment applications, yet the mechanisms underlying water transport within these amorphous polymer materials remain insufficiently understood. To gain more insight into these problems on a microscopic scale, we employ molecular dynamics (MD) simulations to analyze the relationship between the structural properties and the water permeation behavior of PA membranes. Two distinct atomistic models of PA membranes are developed by controlling their degrees of cross-linking (DC). We then conducted a comparative analysis on their microscopic structural properties and configurations of water inside the membranes and investigated how these differences lead to different water diffusion coefficients. Our results reveal that the membrane with a lower DC exhibits higher polymer mobility and a more orderly microscopic structure, allowing the formation of pores that can hold larger water clusters as well as more transient passages between pores, both contributing to an increased water diffusion coefficient. From these observations, we can conclude that water permeability within PA membranes is governed by both the morphology of semirigid pores and the oscillatory movements of the polymer chains. Overall, these findings contribute to a deeper understanding of the intricate mechanisms governing water permeation in PA membranes and may inform the design of more efficient membranes for reverse osmosis and other water treatment technologies.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Flexibility and Essentiality of the Tricarboxylic Acid Cycle in <i>Plasmodium</i>.","authors":"Arpitha Suryavanshi, Anusha Chandrashekarmath, Nivedita Pandey, Hemalatha Balaram","doi":"10.1021/acsinfecdis.4c00788","DOIUrl":"https://doi.org/10.1021/acsinfecdis.4c00788","url":null,"abstract":"<p><p>The complete tricarboxylic acid (TCA) cycle, comprising a series of 8 oxidative reactions, occurs in most eukaryotes in the mitochondria and in many prokaryotes. The net outcome of these 8 chemical reactions is the release of the reduced electron carriers NADH and FADH₂, water, and carbon dioxide. The parasites of the <i>Plasmodium spp</i>., belonging to the phylum Apicomplexa, have all the genes for a complete TCA cycle. The parasite completes its life cycle across two hosts, the insect vector mosquito and a range of vertebrate hosts including humans. As the niches that the parasite invades and occupies in the two hosts vary dramatically in their biochemical nature and availability of nutrients, the parasite's energy metabolism has been accordingly adapted to its host environment. One such pathway that shows extensive metabolic plasticity in parasites of the <i>Plasmodium spp</i>. is the TCA cycle. Recent studies using isotope-tracing targeted-metabolomics have highlighted conserved and parasite-specific features in the TCA cycle. This Review provides a comprehensive summary of what is known of this central pathway in the <i>Plasmodium spp</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated High-Throughput Affinity Capture-Mass Spectrometry Platform with Data-Independent Acquisition.","authors":"Hui Jing, Paul L Richardson, Gregory K Potts, Sameera Senaweera, Violeta L Marin, Ryan A McClure, Adam Banlasan, Hua Tang, James E Kath, Shitalben Patel, Maricel Torrent, Renze Ma, Jon D Williams","doi":"10.1021/acs.jproteome.4c00696","DOIUrl":"https://doi.org/10.1021/acs.jproteome.4c00696","url":null,"abstract":"<p><p>Affinity capture (AC) combined with mass spectrometry (MS)-based proteomics is highly utilized throughout the drug discovery pipeline to determine small-molecule target selectivity and engagement. However, the tedious sample preparation steps and time-consuming MS acquisition process have limited its use in a high-throughput format. Here, we report an automated workflow employing biotinylated probes and streptavidin magnetic beads for small-molecule target enrichment in the 96-well plate format, ending with direct sampling from EvoSep Solid Phase Extraction tips for liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis. The streamlined process significantly reduced both the overall and hands-on time needed for sample preparation. Additionally, we developed a data-independent acquisition-mass spectrometry (DIA-MS) method to establish an efficient label-free quantitative chemical proteomic kinome profiling workflow. DIA-MS yielded a coverage of ∼380 kinases, a > 60% increase compared to using a data-dependent acquisition (DDA)-MS method, and provided reproducible target profiling of the kinase inhibitor dasatinib. We further showcased the applicability of this AC-MS workflow for assessing the selectivity of two clinical-stage CDK9 inhibitors against ∼250 probe-enriched kinases. Our study here provides a roadmap for efficient target engagement and selectivity profiling in native cell or tissue lysates using AC-MS.</p>","PeriodicalId":48,"journal":{"name":"Journal of Proteome Research","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Verticillin A-Loaded Surgical Buttresses Prevent Local Pancreatic Cancer Recurrence in a Murine Model.","authors":"Zeinab Y Al Subeh, Herma C Pierre, Cedric J Pearce, Mark W Grinstaff, Aaron H Colby, Kebin Liu, Nicholas H Oberlies","doi":"10.1021/acs.molpharmaceut.4c00589","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00589","url":null,"abstract":"<p><p>The fungal metabolite verticillin A is a potent and selective histone methyltransferase inhibitor. It regulates apoptosis, the cell cycle, and stress response, and displays potent activity in the suppression of tumor cell growth in several different in vivo models. Verticillin A sensitizes pancreatic cancer cells to anti-PD-1 immunotherapy by regulating PD-L1 expression. However, as with many natural products, delivery and systemic toxicity are challenges that must be overcome to advance their use as a chemotherapeutic. To both reduce systemic toxicity and improve delivery, we report a verticillin A-loaded surgical buttress, which is well-tolerated at a dose as high as 40 mg/kg. In contrast, free verticillin A administered systemically results in toxicity at a dose of 3 mg/kg. The verticillin A-loaded buttress suppresses tumor recurrence in vivo in a safe and dose-dependent manner against a highly aggressive and metastatic model of pancreatic cancer.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semisupervised Contrastive Learning for Bioactivity Prediction Using Cell Painting Image Data.","authors":"David Bushiri Pwesombo, Carsten Beese, Christopher Schmied, Han Sun","doi":"10.1021/acs.jcim.4c00835","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00835","url":null,"abstract":"<p><p>Morphological profiling has recently demonstrated remarkable potential for identifying the biological activities of small molecules. Alongside the fully supervised and self-supervised machine learning methods recently proposed for bioactivity prediction from Cell Painting image data, we introduce here a semisupervised contrastive (SemiSupCon) learning approach. This approach combines the strengths of using biological annotations in supervised contrastive learning and leveraging large unannotated image data sets with self-supervised contrastive learning. SemiSupCon enhances downstream prediction performance of classifying MeSH pharmacological classifications from PubChem, as well as mode of action and biological target annotations from the Drug Repurposing Hub across two publicly available Cell Painting data sets. Notably, our approach has effectively predicted the biological activities of several unannotated compounds, and these findings were validated through literature searches. This demonstrates that our approach can potentially expedite the exploration of biological activity based on Cell Painting image data with minimal human intervention.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":"65 2","pages":"528-543"},"PeriodicalIF":5.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do the Shuffle: Expanding the Synthetic Biology Toolkit for Shufflon-like Recombination Systems.","authors":"Jan Katalinić, Morgan Richards, Alex Auyang, James H Millett, Manjunatha Kogenaru, Nikolai Windbichler","doi":"10.1021/acssynbio.4c00790","DOIUrl":"https://doi.org/10.1021/acssynbio.4c00790","url":null,"abstract":"<p><p>Naturally occurring DNA inversion systems play an important role in the generation of genetic variation and adaptation in prokaryotes. Shufflon invertase (SI) <i>Rci</i> from plasmid R64, recognizing asymmetric <i>sfx</i> sites, has been adopted as a tool for synthetic biology. However, the availability of a single enzyme with moderate rates of recombination has hampered the more widespread use of SIs. We identified 14 previously untested SI genes and their <i>sfx</i> sites in public databases. We established an assay based on single-molecule sequencing that allows the quantification of the inversion rates of these enzymes and determined cross-recognition to identify orthogonal SI/<i>sfx</i> pairs. We describe SI enzymes with substantially improved shuffling rates when expressed in an inducible manner in <i>E. coli</i>. Our findings will facilitate the use of SIs in engineering biology where synthetic shufflons enable the generation of millions of sequence variants <i>in vivo</i> for applications such as barcoding or experimental selection.</p>","PeriodicalId":26,"journal":{"name":"ACS Synthetic Biology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DFT Study of Structural, Electronic, and Charge-Transfer Properties of 2-Naphthol Azo Derivatives: Geometric, Positional, and Substituent Effects.","authors":"Tahmina Haque, Monika Akter Shompa, Khurshida Khayer","doi":"10.1021/acs.jpca.4c06467","DOIUrl":"https://doi.org/10.1021/acs.jpca.4c06467","url":null,"abstract":"<p><p>This work represents a systematic computational study of structural and optoelectronic properties of 24 phenylazo-2-naphthol derivatives using the DFT-B3LYP/6-31 + G(d,p) method. The positional isomers of azo compounds have been designed by introducing an azophenyl unit (with and without substituents) at three different (1-, 3-, and 4-) positions of 2-naphthols. This result shows that depending on the linking position of the azophenyl unit and substituents (NO₂ and maleimide), the <i>cis</i>-azo, <i>trans</i>-azo, and hydrazo forms of our substituted azo derivatives possess distinguished UV-vis absorption and charge-transfer properties compared to unsubstituted Sudan I derivatives. Our MO calculations show that all Sudan-MI azo derivatives exhibit unique intramolecular charge transfer from the 2-naphthol-azo group as a donor to the maleimide (MI) group as an acceptor. Interestingly, whereas the <i>trans</i>-azo and hydrazo forms of Sudan-MI derivatives show ππ*CT and nπ*CT beside the ππ* and nπ* transitions, the <i>cis</i>-azo Sudan-MI derivatives exhibit mixed (nπ* + ππ*)CT along with ππ*CT, ππ*, and mixed (nπ* + ππ*) transitions. The nature and order of the main azo ππ* (S₀ → S₂) and nπ* (S₀ → S₁) transitions alter in Sudan-MI derivatives. The respective substitution of NO₂ and MI groups in Para Red and Sudan-MI series leads to the bathochromic shift of λ_max (due to π → π* transitions) in comparison to unsubstituted Sudan I derivatives, for example, the 4-positional Para Red <i>trans</i>-azo isomer (λ_max 516.9 nm) is 93.8 nm and the 4-positional Sudan-MI <i>trans</i>-azo isomer (λ_max 447.3 nm) is 24.2 nm red-shifted compared to the 4-positional Sudan I <i>trans</i>-azo isomer (λ_max 423.1 nm). The <i>cis</i>-azo forms of all positional isomers having twisted geometries show different UV-vis spectral behaviors. In general, our studies demonstrate how the variation in the structure of azo compounds impacts their optoelectronic properties, which could be useful in electronic devices.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}