ACS Publications最新文献

{"title":"Antibacterial and Angiogenic Copper Phosphate-Modified Carbonate Apatite Honeycomb Plugs for Enhanced Gingival and Alveolar Bone Regeneration.","authors":"Koichiro Hayashi, Eri Teramoto, Ahmad Nazir Taleb Alashkar, Zhanrui Lou, Masafumi Moriyama, Kunio Ishikawa","doi":"10.1021/acsami.5c01022","DOIUrl":"https://doi.org/10.1021/acsami.5c01022","url":null,"abstract":"<p><p>After tooth extraction, socket preservation is essential to minimize alveolar bone loss and improve implant success. However, conventional granular graft materials lack gingival regenerative and antibacterial properties, pose a risk of migration, and often require additional procedures, which complicate treatment and reduce clinical efficacy. To address these limitations, we developed a cylindrical carbonate apatite (CAp) plug with a honeycomb structure surface-modified with copper phosphate (CuP). The CAp composition offers inherent osteoconductivity, while CuP imparts antibacterial and angiogenic properties. The honeycomb structure promotes the ingrowth of bone and blood vessels, while the cylindrical shape enhances surgical handling and minimizes material migration. Together, the optimized composition, structure, and shape contribute to infection prevention and enhanced tissue regeneration. In vitro, the honeycomb plugs with 500 ppm of Cu exhibited strong antibacterial effects against <i>Streptococcus mutans</i> and methicillin-resistant <i>Staphylococcus aureus</i> without cytotoxicity toward human cells. These honeycomb plugs also promoted osteogenic differentiation of mesenchymal stem cells and endothelial cell growth. In vivo, despite migration of CAp granules, the honeycomb plugs remained stable, prevented fibrous tissue invasion, and achieved superior regeneration of both the gingiva and bone. The plugs completely repaired gingival defects and were resorbed and replaced with bone within 4 weeks, eliminating long-term risks associated with residual materials. These results indicate that the developed material effectively addresses the limitations of conventional grafts and demonstrates significant potential for improving clinical outcomes in socket preservation.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifunctional Subnanowires Modulating <i>In Situ</i> Polymerization for High-Voltage Solid-State Batteries.","authors":"Haoran Xu, Hong Zhang, Wei Peng, Shijie Feng, Chenhui Dong, Zixin Xiao, Wei Yang, Ahmed Eissa Abdelmaoula, Salah Abdelghany Eleissawy Salman, Chunhua Han, Lin Xu","doi":"10.1021/acsami.5c00588","DOIUrl":"https://doi.org/10.1021/acsami.5c00588","url":null,"abstract":"<p><p><i>In situ</i> polymerized poly(1,3-dioxolane) (PDOL) electrolytes endow excellent interfacial contact and satisfactory compatibility in lithium metal batteries (LMBs). However, their limited oxidative stability hinders compatibility with high-voltage cathodes. Herein, an effective molecular weight modulation-induced strategy via multifunctional subnanowires (SNWs) was proposed to realize the superior oxidative stability of PDOL electrolytes with narrow molecular weight distribution (MWD). Specifically, the ring-opening polymerization of DOL was promoted by oxygen vacancies (Ov) on SNWs, which enhanced the monomer conversion rate. Simultaneously, the polymerization speed during the <i>in situ</i> process was regulated by the weak adsorption of monomers induced by protonated oleylamine (PO). Furthermore, the dual Lewis acid sites (Ov and PO) of the SNWs facilitate lithium salt dissociation, releasing more movable Li⁺ for transport. Thus, the SNWs-induced polymerized PDOL electrolytes with an MWD of 1.42 exhibit remarkable oxidative stability exceeding 5.1 V while achieving a lithium-ion transference number of 0.81. Consequently, the assembled NCM811||Li cells maintain a stable operation for 100 cycles at 4.5 V with a capacity retention rate of 89.2%. This research first modulates the MWD of <i>in situ</i> polymerized PDOL electrolytes using subnanowires to enhance their oxidative ability, presenting a unique strategy to inspire the development of high-performance LMBs.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling Active-State Conformations of G-Protein-Coupled Receptors Using AlphaFold2 via Template Bias and Explicit Protein Constrains.","authors":"Luca Chiesa, Dina Khasanova, Esther Kellenberger","doi":"10.1021/acs.jcim.5c00489","DOIUrl":"https://doi.org/10.1021/acs.jcim.5c00489","url":null,"abstract":"<p><p>AlphaFold2 and other deep learning tools represent the state of the art for protein structure prediction; however, they are still limited in their ability to model multiple protein conformations. Since the function of many proteins depends on their ability to assume different stable conformational states, different approaches are required to access these alternative conformations. G-protein-coupled receptors regulate intracellular signaling by assuming two main conformational states: an active state able to bind G-protein and an inactive state. Receptor activation is characterized by large conformational changes at the intracellular region, where the G-protein interacts, accompanied by more subtle structural rearrangements at the extracellular ligand-binding site. Retrospective studies have demonstrated that, for many receptors, the inactive state is the favored conformation generated by AlphaFold2 when the receptor is modeled alone, while active-state structures can only be modeled by introducing a conformational bias in the template information used for the prediction or by explicitly incorporating the binding of a ligand into the modeled system. This benchmarking study extends previous analyses, confirming the opportunities of deep learning tools for modeling G-protein complexed to the active state of receptor, while also revealing limitations in the modeling of allosteric effects, particularly the reduced accuracy of predictions at the receptor extracellular site, which may impact their applicability in structure-based drug design.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179615","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":"Transport Properties of Self-Assembling G-Hydrogels: Evidence for a Tunable Fickian Diffusivity.","authors":"Alessia Pepe, Paolo Moretti, Paolo Mariani, Valentina Notarstefano, Francesca Ripanti","doi":"10.1021/acs.jpcb.5c00564","DOIUrl":"10.1021/acs.jpcb.5c00564","url":null,"abstract":"<p><p>The mixing of Guanosine (Gua) and Guanosine 5'-monophosphate (GMP) in water in selected compositions yields highly hydrated, transparent, and self-healing self-assembled supramolecular G-hydrogels, attractive for biomedical applications. This work investigates how hydrogel composition affects solute transport, including diffusion, binding, loading, and release properties, using a set of fluorescent probes with varying size and polarity. Although small/wide-angle X-ray scattering techniques showed that no structural changes are induced by probe addition, even when intercalation into G-quadruplexes is expected, the internal mesh structure of the hydrogel, modulated by the Gua:GMP ratio, directly impacts probe diffusivity and loading. Tighter networks (e.g., 1:1) slow diffusion and enhance retention compared to looser configurations (e.g., 1:4). Moreover, UV-visible titrations revealed markedly different binding affinities (<i>K</i>_b ≈ 5.7 × 10⁴ M^-1 for DAPI, 8.0 × 10³ M^-1 for ThT, and 1.4 × 10² M^-1 for RhB), which are expected to result in lower diffusion coefficients and slower release, especially for DAPI and ThT. Indeed, diffusion coefficients, obtained via fluorescence recovery after photobleaching and time-resolved fluorescence spectroscopy, reach 90, 20, and 60 μm²/s for FITC-dextran, ThT, and RhB, respectively. Probe release kinetics, modeled via Weibull fitting, indicated sustained release with characteristic times (τ) between 9.6 and 23.2 h and β ≈ 1 in 1× PBS, consistent with predominantly Fickian diffusion. Remarkably, switching to 10× PBS significantly accelerated release (τ reduced by ≈ 40-50%), suggesting that ionic strength and/or pH changes critically affect not only probe-hydrogel interactions but also the internal gel architecture, altering porosity, mesh size, and network tortuosity, thus enhancing molecular mobility. Overall, the G-hydrogel system offers a structurally tunable and composition-dependent platform capable of finely regulating molecular transport and release profiles, making it highly suitable for controlled drug delivery and adaptive biomaterial applications.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"5136-5149"},"PeriodicalIF":2.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074949","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":"Size Dependent Liposomal Fusion and H-Bonded Sticky Aggregation Induced by Gold Nanoclusters.","authors":"Mallika Mukherjee, Arunavo Chatterjee, Pradipta Purkayastha","doi":"10.1021/acs.jpcb.5c01053","DOIUrl":"10.1021/acs.jpcb.5c01053","url":null,"abstract":"<p><p>We present a novel approach to quantitatively control liposomal fusion and aggregation, depending upon the surface charge and functionalities, using fluorescent gold nanoclusters (AuNCs). We show that ligand-protected ultrasmall AuNCs are excellent fusogenic materials that follow renal clearance pathways after induction of liposomal fusion, especially with dipalmitoylphosphatidylcholine (DPPC) and 1,2-dimyristoyl-<i>sn</i>-glycero-3-phosphoglycerol (DMPG) mixed in a 3:1 molar ratio mimicking the brain cells. AuNCs show interesting photophysics and emit from visible to near-infrared (NIR) regions depending upon the quantum confinement effect that is directly related to the Fermi wavelength and size of the NCs. Herein, we have synthesized orange-emitting l-glutathione (GSH) coated Au₂₅(GSH)₁₈ NCs (GSH-AuNCs) to be applied on lipid membranes to observe the fusogenic property on small and giant unilamellar vesicles (SUVs and GUVs). We noticed that the GSH-AuNCs easily attach to the surface of the DPPC liposomes and facilitate complete fusion through favorable lipid mixing. The fusion rate is higher (80%) for the DPPC SUVs compared to that for the GUVs, which has been explained experimentally. On the contrary, the DMPG SUVs aggregate, with minimal lipid mixing, in the presence of the GSH-AuNCs. We noted a ∼70% fusion efficiency for SUVs with mixed DPPC:DMPG composition (3:1 molar ratio). This is the first report on fusion and aggregation of liposomes guided by ligand functionalities and surface charge of AuNCs.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"5207-5216"},"PeriodicalIF":2.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092095","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":"Hydrolytic Degradation of Key Plastic Pollutant Model Systems by a Discrete Metal-Oxo Cluster: A Combined Theoretical and Experimental Study.","authors":"Leonardo F Serafim, Francisco de Azambuja, Parth Rathee, Lukun Wang, Tatjana N Parac-Vogt, Rajeev Prabhakar","doi":"10.1021/acs.jpcb.5c01255","DOIUrl":"10.1021/acs.jpcb.5c01255","url":null,"abstract":"<p><p>Degradation of plastic materials represents one of the major challenges faced by the modern world. In this study, computational and experimental techniques have been employed to investigate the hydrolysis of most commonly used plastic materials poly(ether urethane) (PEU) and polyethylene terephthalate (PET) and their commercially available models ethyl <i>N</i>-phenylcarbamate (ENP) and ethylene glycol dibenzoate (EGD), respectively, by a discrete metal-oxo cluster, Zr-substituted Keggin-type polyoxometalate, (Et₂NH₂)₈[Zr(μ-O)(H₂O)(PW₁₁O₃₉)] (<b>ZrK</b>), in which the Zr(IV) catalytic site is stabilized by coordination to a robust metal-oxo core. The all-atom molecular dynamics simulations predicted that all substrates interact with <b>ZrK</b> through water-mediated interactions. The quantum mechanics/molecular mechanics (QM/MM) calculations showed that the lengths of scissile ester and amide bonds of PEU/ENP and the ester bond of PET/EGD are quite similar, and the hydrolysis of PEU and ENP and PET and EGD occurs with similar energetics. According to the most plausible mechanisms, the cleavage of the ester and amide bonds of PEU/ENP takes place with a barrier of 16.5/16.6 and 19.0/20.4 kcal/mol, respectively. However, the scissile ester bond of PET/EGD is hydrolyzed with a barrier of 16.7/16.5 kcal/mol. This computed difference in the rate-limiting barrier of 3.9 kcal/mol between the amide bond of ENP and the ester bond of EGD is supported by the experimentally observed sluggish hydrolysis of ENP in comparison to EGD. While both ENP and EGD were successfully hydrolyzed by <b>ZrK</b> in DMSO solvent at 100 °C, EGD hydrolysis has proven to be much more efficient, with 99% yield obtained within 18 h compared to 48% of ENP hydrolysis observed after 162 h. The combined theoretical and experimental results presented here contribute to the development of potent and robust all-inorganic cluster-based catalysts for the degradation of PEU and PET and suggest that ENP and EGD can be used as excellent model substrates in this endeavor.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"5268-5283"},"PeriodicalIF":2.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100997","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":"Codelivery of Cell Apoptosis AVPIAQ Peptide and Doxorubicin for Synergistic Cancer Therapy.","authors":"Yonghui Liu, Zongqian Ren, Yu Zhao, Dong Wan, Jie Pan","doi":"10.1021/acsabm.5c00607","DOIUrl":"https://doi.org/10.1021/acsabm.5c00607","url":null,"abstract":"<p><p>Conventional combination chemotherapy, which utilizes noncovalent bonding for self-assembly and encapsulation for drug loading and delivery, faces challenges in clinical application. The development of combination chemotherapy systems that enable multiple drugs to be contained within a single molecule to achieve synergistic therapy is an innovative concept for cancer treatment. In this study, a polymeric micelle named mPEG-GFLGAVPIAQDEVD-DOX&DOX was constructed through the covalent linkage of two chemotherapy drugs of doxorubicin (DOX) and the pro-apoptotic peptide SMAC (AVPIAQ) and then using the thin-film hydration method. The micelle can be specifically recognized by cathepsin B within cancer cells, leading to the cleavage of the peptide GFLG. This action facilitates the shedding of mPEG, thereby enhancing the efficiency of micelle uptake by cells. Upon internalization, the micelles release the encapsulated DOX, thereby promoting apoptosis and activating Caspase-3, which in turn cleaves the peptide DEVD. This process accelerates the release of DOX, thereby enhancing the efficacy of tumor cell killing. Subsequently, the pro-apoptotic peptide SMAC was exposed, which bonded to inhibitors of apoptosis proteins (IAPs) and inhibited their antiapoptotic activity, thereby accelerating tumor cell apoptosis. SMAC plays a key role in apoptosis by alleviating the inhibitory effect of IAPs on Caspase-3, allowing DOX and SMAC to act synergistically on tumor cells as cocktail therapy, achieving a double-killing effect, thereby improving therapeutic efficacy against tumors. These results indicated that the dual-drug polymer micelles prepared can significantly enhance antitumor therapeutic efficacy and reduce their side effects.</p>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping of Mycobacterial Enzymes Involved in Triacylglycerol Accumulation as Intrabacterial Lipid Inclusions Using Activity-Based Multitarget Inhibitor Probes.","authors":"Romain Avellan, Jordan Lehoux, Thomas Francis, Tonia Dargham, Léa Celik, Alexandre Guy, Isabelle Poncin, Vanessa Point, Laurent Kremer, Thierry Durand, Stéphane Audebert, Luc Camoin, Christopher Spilling, Pierre Santucci, Céline Crauste, Stéphane Canaan, Jean-François Cavalier","doi":"10.1021/acsinfecdis.5c00127","DOIUrl":"https://doi.org/10.1021/acsinfecdis.5c00127","url":null,"abstract":"<p><p>Lipids play a critical role in the physiology, life cycle, and pathogenicity of mycobacteria. They largely participate in host-pathogen interactions and fulfill important functions ranging from cell wall biosynthesis/maintenance, bacterial growth dynamics, and long-term persistence. In that context, triacylglycerol, a specific subtype of neutral lipid, is stored as intrabacterial lipid inclusions (ILI), which have been described as important structures for long-term survival and persistence within the host. However, the enzymes involved in ILI formation and degradation remain largely undefined. Using bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP) of newly synthesized oxadiazolone (<b>OX</b>), cyclophostin, and cyclipostins (<b>CyC</b>) probes, we report the direct capture of target proteins in <i>Mycobacterium abscessus</i> growing under carbon excess and nitrogen-deprived in vitro conditions that promote triacylglycerol production and ILI formation. This approach led to the identification of a set of 65 enzymes potentially involved in global processes related to ILI anabolism. Among these, the long-chain-fatty-acid--CoA ligase MAB_1978c/FadD15 has been validated as a pivotal enzyme that colocalizes on ILI and as a major contributor in ILI formation in <i>M. abscessus</i>.</p>","PeriodicalId":17,"journal":{"name":"ACS Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172078","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":"Refining the Amino Reactivity-Based Identification of Respiratory Sensitizers.","authors":"Martin Simoneit, Helene Langer, Nadin Ulrich, Alexander Böhme","doi":"10.1021/acs.chemrestox.4c00545","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00545","url":null,"abstract":"<p><p>The sensitization of the respiratory tract may lead to various pulmonary diseases such as asthma. It can be triggered by the chemical reaction of organic electrophiles with nucleophiles of lung proteins with amino groups being of particular interest in this case. For assessing the dermal sensitization potential of chemicals, the direct peptide reactivity assay (DPRA) has become an OECD-accepted nonanimal test system. However, issues with the identification of known respiratory sensitizers such as isocyanates and anhydrides based on their amino reactivity in the DPRA have been reported. Hence, in this study the chemoassay employing glycine-<i>para</i>-nitroanilide (Gly-pNA) as model nucleophile is applied to eight iso(thio)cyanates, seven anhydrides, four dinitrobenzenes, one triazine, five acrylates, glutaraldehyde, and chloramine T to quantify their amino reactivity in terms of the second order rate constant <i>k</i>_Gly and the DPRA-like 24 h percent depletion <i>D</i>_Gly. A comparison of <i>D</i>_Gly with respective DPRA amino reactivity data (<i>D</i>_DPRA) showed that in particular iso(thio)cyanates and anhydrides are substantially more reactive toward Gly-pNA. This can be rationalized by the unintentional and so far not considered reaction of the test compounds with the ammonium acetate buffer used for DPRA testing. A detailed analysis of this reaction includes half-lives and analytically determined adduct patterns and indicates that it can hamper the envisaged depletion of the DPRA amino nucleophile. Finally, the obtained log <i>k</i>_Gly values range from -3.73 to ≥ 4.52 and allow for an improved identification of respiratory sensitizers. Hence, the Gly-pNA chemoassay may serve as a nonanimal screening method as one part of a mechanism-informed integrated testing and assessment strategy for respiratory sensitizers.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tables Turned─Structural Mechanisms of Target-Induced miRNA Destabilization.","authors":"Ukesh Karki, Prem Chapagain","doi":"10.1021/acs.jpcb.5c01093","DOIUrl":"10.1021/acs.jpcb.5c01093","url":null,"abstract":"<p><p>Argonaute 2 (Ago2) loaded with a microRNA (miRNA) forms an RNA-induced silencing complex (RISC), which targets mRNA through miRNA-mRNA base pairing, leading to translation inhibition or degradation of the target mRNA. However, certain target mRNAs can turn the table by binding to the miRNA-Ago complex with high complementarity, resulting in the destruction of the miRNA itself, and the process is commonly known as target-directed miRNA degradation (TDMD). Highly complementary targets can also promote miRNA destabilization and release from Ago2. However, the dynamic nature of the target-induced effects of miRNA-Ago2 interactions and miRNA dissociation from Ago2 is not well understood. The lack of a complete crystal structure of the complex involved in TDMD has limited computational study of the dynamics of target or miRNA destabilization. In this work, we utilized AlphaFold 3 (AF3) to model the full structures of Ago2-miR-27a-mRNA-target complexes and investigated the dynamics of miRNA-mRNA and miRNA-Ago2 interactions using molecular dynamics simulations. We chose miR-27a because it has not only been extensively investigated for its involvement in cancer biology but it is also a known target for its degradation via TDMD by viral mRNAs such as HVS HSUR1 from Herpesvirus saimiri. We systematically changed the targets from seed-only base pairing (target ATF3) to seed and extensive supplementary base pairing (target HVS HSUR1) to compare the stability of the miRNA-Ago2 complexes. We find that the sequence complementarity in seed, central, and supplementary pairings as well as the structural agility of Ago2 allow for differential stability of miRNA binding, potentially facilitating dissociation under different conditions.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":"5166-5175"},"PeriodicalIF":2.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953379","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}