Journal of Biomolecular Structure & Dynamics最新文献

{"title":"Amino acid osmolytes disrupting intradomain interactions reduce the amyloidogenicity of α-synuclein: studies with charged l-amino acids and their derivatives.","authors":"Archi Saurabh, Suraj Chauhan, Jogadhenu S S Prakash, N Prakash Prabhu","doi":"10.1080/07391102.2025.2543362","DOIUrl":"https://doi.org/10.1080/07391102.2025.2543362","url":null,"abstract":"<p><p>Aggregation of α-synuclein (α-syn) is a hallmark of Parkinson's and dementia with Lewy bodies pathogenesis. The high plasticity and lack of stable tertiary structure make α-syn more susceptible to its surrounding environment. Under stress conditions, small organic molecules known as osmolytes accumulate inside the cells. They affect the conformational states and fibrillation pathways of proteins. Here, the effects of eight different amino acid osmolytes (charged: l-glutamate, l-aspartate, l-lysine, l-arginine; amide side chains: l-glutamine, l-asparagine; and <i>N</i>-acetylated: <i>N</i>-acetyl-l-glutamic acid, <i>N</i>-acetyl-l-lysine) on the fibrillation of human α-synuclein were examined. Arginine and <i>N</i>-acetyl-l-lysine inhibited the fibrillation at concentrations above 0.2 and 0.4 M, respectively. Lysine, asparagine, and glutamate accelerated the fibrillation by reducing lag time. <i>N</i>-acetyl-l-glutamic acid induced lag-independent fibrillation, whereas glutamine and asparagine showed concentration-dependent effects on the fibrillation with reduced lag time at higher concentrations. Molecular dynamics simulations revealed that interdomain contacts facilitated the fibrillation. The amino acids interacting predominantly through van der Waals interactions reduced the lag time of α-syn. However, the amino acids having strong electrostatic interactions with the protein disrupted intradomain contacts, favored extended conformation, and inhibited the fibril formation.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-24"},"PeriodicalIF":2.4,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared regulatory factors influencing mRNA translation rate and half-life in yeast.","authors":"Sudipto Basu, Suman Hait, Sudip Kundu","doi":"10.1080/07391102.2025.2540787","DOIUrl":"https://doi.org/10.1080/07391102.2025.2540787","url":null,"abstract":"<p><p>Extensive research has highlighted the role of codon composition in regulating co-translational mRNA decay. Translational efficiency is often measured using a codon usage metric like the codon adaptation index (CAI), while mRNA stability is assessed through sequence- and structure-dependent metrics such as codon stabilization coefficient and internal unstructured segments (IUS). However, the question remains whether sequence-dependent translation parameters can influence mRNA stability, or if stability-related parameters can, in turn, regulate mRNA translation and overall co-translational decay. Our approach integrates yeast mRNA sequence, structural, and ribosomal density (RD) data to explore the interconnected regulatory determinants that govern mRNA translation and degradation. Our findings offer new insights into how codon preferences and mRNA structuredness impact these processes, with CAI predominantly shaping translation rates and IUS affecting mRNA decay. Additionally, we observe that the impact of RD on co-translational mRNA decay is context-specific, depending on the dynamics of the primary regulators. These primary regulators are conserved across the genome and throughout evolution, emphasizing their importance in maintaining cellular function. We propose that optimizing both CAI and IUS is essential for improving mRNA-based drug delivery systems. A deeper understanding of the relationship between these factors could lead to more effective mRNA therapeutics.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.4,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating diffusion models and molecular modeling for PARP1 inhibitors generation.","authors":"Tan Khanh Nguyen, Thi-Thu Nguyen, Khanh Huyen Thi Pham, Manh-Tu Luong, Ho Trong Tai, Dao Thi Tuyet Mai, Nhat-Hai Nguyen","doi":"10.1080/07391102.2025.2544217","DOIUrl":"https://doi.org/10.1080/07391102.2025.2544217","url":null,"abstract":"<p><p>Molecule generation is a critical task in drug discovery, with growing interest in using deep learning to design new compounds. In this study, we propose a novel approach to generate potential PARP1 inhibitors by combining diffusion-based generative models with molecular modeling techniques. Starting from the ZINC20 database, we used diffusion models to create new compounds and applied a predictive model to estimate their PARP1 inhibitory activity. Promising candidates were further evaluated using molecular docking and molecular dynamics simulations to assess their binding affinity. Our results demonstrate the potential of this integrated method to discover novel scaffolds for PARP1 inhibition, supporting future efforts in targeted cancer therapy development.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.4,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of temperature on the structure of α-l-fucosidase from <i>Thermotoga maritima</i>: implications from molecular dynamics simulation.","authors":"Mónica A Robles-Arias, Carlos Jímenez-Pérez, Carlos Z Gómez-Castro, Sergio Alatorre-Santamaría, Francisco Guzmán-Rodríguez, Mariano García-Garibay, Lorena Gómez-Ruiz, Gabriela Rodríguez-Serrano, Salvador R Tello-Solís, Alma E Cruz-Guerrero","doi":"10.1080/07391102.2025.2543365","DOIUrl":"https://doi.org/10.1080/07391102.2025.2543365","url":null,"abstract":"<p><p>Human milk oligosaccharides, like 2'-fucosyllactose, have beneficial effects on newborn health, and they can be obtained by enzymatic synthesis with α-l-fucosidases. In this work, the impact of temperature on the α-l-fucosidase from <i>Thermotoga martima</i> (TmαFuc) structure was evaluated using molecular dynamics simulation (MD). The TmαFuc was found stable in a temperature range of 333-368 K since no differences in the RMSD, RMSF, H-bonds, solvent accessible surface area, radius of gyration, salt bridges and native contacts (<i>Q</i>) values were observed. Elevated temperature did not affect the protein secondary fold; nevertheless, increasing temperature to 473 K decreased the stabilizing structure, such as α-helices and β-sheets, and increased the presence of irregular structures. Eventually, these conformational changes caused the loss of enzymatic activity at high temperatures. Additionally, the MD results showed that the enzyme active site could adopt the following conformations: open, intermediate, or closed; these conformations are needed first to retain the substrates in the transglycosylation activity, such as the donor and the acceptor and then to release the transfructosylated product. Furthermore, Free Energy Landscape analysis showed that the increment in temperature facilitates the enzyme to fluctuate between conformational states, and that the system moves freely between states, suggesting frequent conformational transitions.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the impact of serine phosphorylation flanking the KxGS motif in the repeat 3 domain of human tau on tubulin detachment.","authors":"Selvaa Kumar C, Subha Yegnaswamy, Debjani Dasgupta, Parul Johari, Mahalakshmi Harish","doi":"10.1080/07391102.2025.2543373","DOIUrl":"https://doi.org/10.1080/07391102.2025.2543373","url":null,"abstract":"<p><p>Tau, a highly disordered protein, comprises four repeat domains (R1-R4) essential for tubulin binding and structural stability. Post-translational modifications, such as the phosphorylation of serine residues within these repeat domains, regulate the tau protein's association and dissociation with tubulin protein. Notably, the detachment of tau from tubulin following phosphorylation contributes to neurofibrillary tangle formation within neurons, a hallmark of Alzheimer's disease. Despite its significance, the structural alterations induced by phosphorylation and their impact on these domains remain poorly understood. The present <i>in silico</i> study investigates the structural effects of phosphorylation at Ser305 (R2 domain), adjacent to the PGGG motif, and Ser320 (R3 domain), near the regulatory KxGS motif, through docking and simulation studies. The findings indicate that phosphorylation at Ser305 enhances tubulin binding more effectively than phosphorylation at Ser320. Alternatively, this finding was validated by binding the aggregator inducer, heparin, to tau. The results confirmed that Ser320-phosphorylated tau exhibited stronger binding than Ser305-phosphorylated tau protein. Altogether, these results suggest that Ser320-phosphorylated tau enhances the tau protein's propensity to aggregate more by strongly binding to heparin and activating the detachment process through weakly binding to tubulin. Thus, this study suggests that structural changes following phosphorylation at Ser305 might be non-pathogenic, whereas phosphorylation at Ser320 could be pathogenic, contributing to adverse effects. A deeper understanding of the role of phosphorylation in the tau-tubulin detachment mechanism could aid in the development of novel inhibitors to regulate tau aggregation and prevent neurofibrillary tangle formation.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-19"},"PeriodicalIF":2.4,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutation-specific structural changes in BRAF: understanding dimerization and drug binding for targeted therapy.","authors":"Minjie Zhao, Rabia Zafar, Saad Serfraz, Kun Wu","doi":"10.1080/07391102.2025.2543358","DOIUrl":"10.1080/07391102.2025.2543358","url":null,"abstract":"<p><p>The dimerization of BRAF with CRAF is a critical regulatory mechanism within the MAPK/ERK signaling cascade, and its disruption by mutations in the BRAF kinase domain contributes to tumorigenesis across various cancers. While wild-type BRAF depends on RAS-mediated dimerization for activation, oncogenic mutations alter this dependency, impacting structural conformation, ATP/drug binding, and downstream signaling. Despite extensive functional data, the structural and biophysical consequences of these mutations remain poorly defined. Here, we examine five BRAF mutations oncogenic (V600E, G469E, D594G) and benign (N581S, E586K) through molecular dynamics simulations, ATP-binding assessments, and drug interaction analyses involving Sorafenib and U0126. Our results suggest that V600E stabilizes the activation loop in an active, monomeric form, bypassing dimerization and conferring resistance to Sorafenib. G469E retains dimerization dependence, shows intermediate activity, and exhibits moderate drug responsiveness. D594G, a kinase-inactive mutant, functions as a scaffold for CRAF activation, with transient ATP-induced stabilization but minimal Sorafenib sensitivity. Benign variants maintain wild-type-like structural integrity, dimer stability, and inhibitor response. Simulations highlight mutation-specific effects on key regions, including the P-loop, DFG motif, and catalytic loop, and reveal distinct conformational landscapes through free energy and compactness analyses. Our findings provide a mechanistic framework linking structure to function in BRAF mutants, supporting mutation-guided therapeutic strategies in precision oncology.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-19"},"PeriodicalIF":2.4,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1080/07391102.2025.2542701","DOIUrl":"https://doi.org/10.1080/07391102.2025.2542701","url":null,"abstract":"","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1"},"PeriodicalIF":2.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In-silico</i> and <i>in-vitro</i> evaluation of antifungal bioactive compounds from <i>Streptomyces</i> sp. strain 130 against <i>Aspergillus flavus</i>.","authors":"Munendra Kumar, Parveen, Nafis Raj, Shabana Khatoon, Khalid Umar Fakhri, Prateek Kumar, Mubarak A Alamri, Mehnaz Kamal, Nikhat Manzoor, Harsha, Renu Solanki, Gehan M Elossaily, Yahya I Asiri, Mohd Zaheen Hassan, Monisha Khanna Kapur","doi":"10.1080/07391102.2024.2313167","DOIUrl":"10.1080/07391102.2024.2313167","url":null,"abstract":"<p><p><i>Streptomyces</i> spp. are considered excellent reservoirs of natural bioactive compounds. The study evaluated the bioactive potential of secondary metabolites from <i>Streptomyces</i> sp. strain 130 through PKS-I and NRPS gene-clusters screening. GC-MS analysis was done for metabolic profiling of bioactive compounds from strain 130 in the next set of experiments. Identified antifungal compounds underwent ADMET analyses to screen their toxicity. All compounds' molecular docking was done with the structural gene products of the aflatoxin biosynthetic pathway of <i>Aspergillus flavus</i>. MD simulations were utilized to evaluate the stability of protein-ligand complexes under physiological conditions. Based on the <i>in-silico</i> studies, compound 2,4-di-tert butyl-phenol (DTBP) was selected for <i>in-vitro</i> studies against <i>Aspergillus flavus</i>. Simultaneously, bioactive compounds were extracted from strain 130 in two different solvents (ethyl-acetate and methanol) and used for similar assays. The MIC value of DTBP was found to be 314 µg/mL, whereas in ethyl-acetate extract and methanol-extract, it was 250 and 350 µg/mL, respectively. A mycelium growth assay was done to analyze the effect of compounds/extracts on the mycelium formation of <i>Aspergillus flavus</i>. In agar diffusion assay, zone of inhibitions in DTBP, ethyl-acetate extract, and methanol extract were observed with diameters of 11.3, 13.3, and 7.6 mm, respectively. In the growth curve assay, treated samples have delayed the growth of fungi, which signified that the compounds have a fungistatic nature. Spot assay has determined the fungal sensitivity to a sub-minimum inhibitory concentration of antifungal compounds. The study's results suggested that DTBP can be exploited for antifungal-drug development.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6045-6063"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the molecular interaction of hepatitis B virus inhibitor, entecavir with human serum albumin through computational, microscopic and spectroscopic approaches.","authors":"Mujaheed Abubakar, Saharuddin B Mohamad, Adyani Azizah Abd Halim, Saad Tayyab","doi":"10.1080/07391102.2024.2311331","DOIUrl":"10.1080/07391102.2024.2311331","url":null,"abstract":"<p><p>Molecular docking, molecular dynamics (MD) simulation, atomic force microscopy (AFM) and multi-spectroscopic techniques were selected to unveil the molecular association between the hepatitis B virus (HBV) inhibitor, entecavir (ETR), and the major blood plasma transporter, human serum albumin (HSA). The entire docking and simulation analyses recognized ETR binding to subdomain IIA (Site I) of HSA through hydrogen bonds, hydrophobic and van der Waals forces while maintaining the complex's stability throughout the 100 ns. A gradual lessening in the Stern-Volmer quenching constant (<math><mrow><msub><mrow><mi>K</mi></mrow><mrow><mtext>sv</mtext></mrow></msub></mrow></math>) with rising temperatures registered ETR-induced quenching of HBV fluorescence as static quenching, thus advising complexation between ETR and HSA. The further advocation of this conclusion was seen from a larger value of the biomolecular quenching rate constant ((<math><mrow><mtext>kq</mtext></mrow></math>) > 10¹⁰ M^-1s^-1), changes in the spectra (UV-Vis absorption) of HSA following ETR inclusion and ETR-induced swelling of HSA in the AFM results. The ETR appeared to bind to HSA with moderate affinity (<math><mrow><msub><mrow><mi>K</mi></mrow><mrow><mi>a</mi></mrow></msub></mrow><mo>=</mo><mn>1.87</mn><mo>-</mo><mn>1.19</mn><mo>×</mo><mrow><msup><mrow><mn>10</mn></mrow><mrow><mn>4</mn></mrow></msup></mrow><mi> </mi></math>M^-1) at 290, 300 and 310 K. Significant alterations in the protein's secondary and tertiary structures, including changes in the protein's Tyr/Trp microenvironment, were also detected by circular dichroism and three-dimensional fluorescence spectra when the protein was bound to ETR. The findings of the drug displacement study backed the docking results of Site I as ETR's preferred binding site in HSA.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"6012-6025"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of 4-sulfamoyl phenyl diazocarboxylic acid derivatives as novel non-classical inhibitors of human carbonic anhydrase II activity: an <i>in vitro</i> study.","authors":"Nima Fatahian Bavandpour, Maryam Mehrabi, Hadi Adibi, Masomeh Mehrabi, Reza Khodarahmi","doi":"10.1080/07391102.2024.2310777","DOIUrl":"10.1080/07391102.2024.2310777","url":null,"abstract":"<p><p>The first class of carbonic anhydrase inhibitors (CAIs) discovered was sulfonamides, but their clinical use is limited due to side effects caused by their inhibition of multiple CA isoforms. To overcome this, researchers have focused on developing isoform-selective CAIs. This study involved the synthesis and characterization of novel carboxylic acid/sulfonamide derivatives. We investigated the interaction between these compounds and the human carbonic anhydrase II (hCA II) isoform using spectroscopic and computational methods. The synthesized compounds were evaluated based on their IC₅₀, <i>K</i>_d and <i>K</i>_i values, and it was found that the inhibitory potency and binding affinity of the compounds increased with the number of carboxylic acids zinc binding groups. Specifically, the compound C4, with three carboxylic acid groups, showed the strongest inhibitory potency. Fluorescence measurements revealed that all compounds quenched the intrinsic fluorescence of hCA II through a dynamic quenching process, and each compound had one binding site in the hCA II structure. Thermodynamic analysis indicated hydrogen bonds and van der Waals interactions played key roles in the binding of these compounds to hCA II. Docking studies showed that the carboxylic acid groups directly attached to the zinc ion in the active site, displacing water/hydroxide ions and causing steric hindrance. Overall, the strengthening of inhibitory activity and the binding power of these carboxylic acid derivatives for the hCA II makes these compounds interesting for designing novel hCA II inhibitors.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"5686-5700"},"PeriodicalIF":2.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}