Journal of Biomolecular Structure & Dynamics最新文献

{"title":"Identification of potential 3CLpro inhibitors-modulators for human norovirus infections through an advanced virtual screening approach.","authors":"Shovonlal Bhowmick, Tapan Kumar Mistri, Mohammad K Okla, Ibrahim A Saleh, Achintya Saha, Pritee Chunarkar Patil","doi":"10.1080/07391102.2025.2502672","DOIUrl":"https://doi.org/10.1080/07391102.2025.2502672","url":null,"abstract":"<p><p>The present study aimed to screen small molecular compounds such as human noroviruses (HuNoV) inhibitors/modulators that could potentially be responsible for exhibiting some magnitude of inhibitory/modulatory activity against HuNoV 3CLPro. The structural similarity-based screening against the ChEMBL database is performed against known chemical entities that are presently under pre-clinical trial. After the similarity search, remaining molecules were considered for molecular docking using SCORCH and PLANTS. On detailed analyses and comparisons with the control molecule, three hits (CHEMBL393820, CHEMBL2028556, and CHEMBL3747799) were found to have the potential for HuNoV 3CLpro inhibition/modulation. The binding interaction analysis revealed several critical amino acids responsible to hold the molecules tightly at the close proximity site of the catalytic residues of HuNoV 3CLpro. Further, MD simulation study was performed in triplicate to understand the binding stability and potentiality of the proposed molecule toward HuNov 3CLpro. The binding free energy based on MM-GBSA has revealed their strong interaction affinity with 3CLpro.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-17"},"PeriodicalIF":2.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078378","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":"Computational insights into mutation-induced binding changes in Bruton's Tyrosine Kinase with non-covalent inhibitors.","authors":"Justice Josiah Mallen, Shilpa Sharma, Md Nazmul Hasan, Arjun Saha","doi":"10.1080/07391102.2025.2502140","DOIUrl":"https://doi.org/10.1080/07391102.2025.2502140","url":null,"abstract":"<p><p>Kinases are pivotal in regulating signaling pathways, and their dysregulation is associated with various diseases, including cancers, making them prime therapeutic targets. Bruton's Tyrosine Kinase (BTK) is crucial for B-cell development, and BTK inhibitors have proven effective in treating B-cell malignancies like Chronic Lymphocytic Leukemia (CLL). Non-covalent inhibitors offer a promising therapeutic approach by avoiding covalent bond formation with the protein. However, therapeutic resistance due to BTK mutations in the catalytic domain has led to relapses and refractory cases in CLL, highlighting the need for a deeper understanding of these mutations' impact on treatment outcomes. This study investigates the effects of four prevalent single-point mutations-A428D, T474I, C481S, and L528W-within the catalytic domain of BTK. Using 12.5 microseconds of molecular dynamics simulations and computational drug discovery methods, we examine how these mutations influence the binding affinities and interactions of non-covalent BTK inhibitors. Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) analysis showed that mutant forms of BTK significantly decreased ligand binding free energies compared to the wild types, with a few exceptions. With pocket volume and solvent-accessible surface area analysis, we also show that mutations reduce the binding pocket volume, forcing the inhibitors to move out of the pocket, disrupting the critical non-covalent interactions of the inhibitors with mutant BTK. This confirms the experimental and clinical observations of why these BTK mutations impair inhibitor efficacy fostering drug resistance. Our results offer vital insights for designing next-generation BTK inhibitors to overcome resistance and enhance therapeutic outcomes in B-cell malignancies.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-17"},"PeriodicalIF":2.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078350","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":"Phenotypic and molecular insights into a <i>cypovirus</i> isolated from <i>Antheraea assamensis</i> Helfer (<i>Lepidoptera: Saturniidae</i>) and modelling of its polyhedrin protein structure.","authors":"Surajit Basak, Kangkon Saikia, Aditya Narayan Konwar, Rahul P Hepat, Aparup Patra, Rajiv Borah, Jamie Bojko, Ashis Kumar Mukherjee, Debajit Thakur","doi":"10.1080/07391102.2025.2501674","DOIUrl":"https://doi.org/10.1080/07391102.2025.2501674","url":null,"abstract":"<p><p><i>Antheraea assamensis</i> Helfer (<i>A. assamensis</i>) or Muga silkworm is popularly known for producing golden silk and endemic to the region of Northeast India. The present work characterizes a <i>cypovirus</i> variant infecting <i>A. assamensis</i> larvae, exhibiting characteristic symptoms of flacherie disease. Scanning electron microscope and transmission electron microscope imaging revealed the presence of polyhedral occlusion bodies (OBs) and virion particles measuring 40-50 nm in size. The cypovirus strain comprised of 10 dsRNA genome segments, which were sequenced, assembled and annotated. The encoded viral proteins from different genomic fragments were studied. The phylogenetic analysis of the RNA-dependent RNA polymerase and polyhedrin revealed a close relationship with the previously classified Antheraea mylitta cypovirus 4. The strain was characterized as Antheraea assamensis cypovirus 4 (AaCPV4) with substantial genomic and proteomic evidence that was previously unexplored. The peptide fingerprints of the polyhedrin protein were analysed in the diseased and healthy silkworm lysate by using LC-MS/MS. The polyhedrin protein of AaCPV4 was modelled by different <i>in silico</i> methods and compared with the previously reported cypovirus strains. The multimeric models of polyhedrin were studied and demonstrated the mechanism of formation of OB geometry. Our study provides new insights into the complete genome of AaCPV4 and its viral proteins, which were previously unknown. The present work will help in understanding the differentiation of CPV4 variants infecting <i>Antheraea</i> species and different host adaptations.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078386","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":"Design and synthesis of new benzimidazole-hybrids as anti-microbial agents: exploring the mechanistic insights as DNA gyrase inhibitors via <i>in silico</i> and <i>in vitro</i> based studies.","authors":"Anand Maurya, Upendra Kumar Patel, Punit Tiwari, Gaurav Joshi, Roshan Kumar, Ragini Tilak, Alka Agarwal","doi":"10.1080/07391102.2025.2501669","DOIUrl":"https://doi.org/10.1080/07391102.2025.2501669","url":null,"abstract":"<p><p>Two series of antibacterial agents, 1,2,3-triazole and aminopyrimidine benzimidazole hybrids, were designed, synthesized, and characterized by IR, NMR, Mass spectroscopy, and X-ray crystallography studies. The biological studies revealed that compounds <b>5a</b>, <b>5b</b>, <b>5c</b>, <b>5d</b>, <b>5e</b>, <b>5f</b>, <b>5g</b>, <b>5h</b>, <b>8d</b>, <b>8e</b>, <b>9d</b>, <b>9e</b>, <b>9f</b>, <b>9h</b>, <b>9j</b>, and <b>9k</b> exhibited significant antibacterial activity <i>in vitro</i> compared to the standard drug ciprofloxacin, against Gram-positive and Gram-negative bacterial strains. The study of hemotoxicity displayed a negligible toxicity profile for all the compounds. Furthermore, the mechanistic insights predicted <i>via</i> molecular docking studies on DNA gyrase revealed (Glide Scores) that compounds <b>5c</b> and <b>5f</b> possess better affinity within the active domain of DNA gyrase, which was further corroborated using molecular dynamics followed by direct DNA gyrase-based inhibition assays. Compound <b>5f</b> was the most potent, while <b>5c</b> showed an equipotent inhibition compared to a standard drug.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-20"},"PeriodicalIF":2.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998083","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":"Bioassay-guided isolation of a new cytotoxic compound targeting carbonic anhydrase-II: <i>in-vitro</i> structure-activity relationships and dynamics studies.","authors":"Rabia Maqsood, Saeed Ullah, Faizullah Khan, Muhammad Waqas, Sobia Ahsan Halim, Ajmal Khan, Javid Hussain, Usama Qayum, Simon Gibbons, Najeeb Ur Rehman, Amjad Hussain, Ahmed Al-Harrasi","doi":"10.1080/07391102.2025.2500680","DOIUrl":"https://doi.org/10.1080/07391102.2025.2500680","url":null,"abstract":"<p><p>Bioassay-guided isolation of <i>Anogeissus dhofarica</i> A.J. Scott afforded one new natural product (lupeol butyl ether, <b>1</b>), along with sixteen known metabolites (<b>2</b>-<b>17</b>) reported from this source for the first time. Structural elucidation of the isolates was performed by NMR and mass spectrometry. An <i>in vitro</i> carbonic anhydrase-II (CA-II) inhibition assay was performed on the crude extract, the fractions, and the resulting pure constituents. The activity against CA-II of the crude extract and fractions was in the range of IC₅₀ 45.10-102.56 µg/mL. Among the isolates, <b>14</b> was the most active with an IC₅₀ of 7.19 ± 0.20 µM followed by <b>10</b> (IC₅₀ = 13.61 ± 0.30 µM), <b>12</b> (IC₅₀ = 17.30 ± 0.58 µM) and <b>1</b> (21.63 ± 0.48 µM), with the remaining compounds having moderate to low inhibition. Fourteen compounds were evaluated against breast cancer (MDA-MB-231) and normal cell (3T3-L1) lines in an MTT assay, with most natural products exhibiting moderate activity against MDA-MB-231 cells (<b>1</b>, IC₅₀ = 34.5 ± 0.8 μM/mL), and less active to the normal cell line. Additionally, the molecular binding of the active hits was predicted through an in-silico approach, specifically docking molecular dynamic (MD) simulations, which revealed that acetate and carboxyl moieties play an important role in ligand binding with the Zn²⁺ ion of the CA-II active site. The MD simulation of the structure dynamics revealed that the most active inhibitors (<b>10</b> and <b>14</b>) had strong affinity with the CA-II active site and brought structural conformational changes to the protein.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-17"},"PeriodicalIF":2.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993472","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":"Analysis of the bonding affinities between human PSGL-1 and Vpu derived from the different HIV-1 groups - in silico insights.","authors":"Silvere D Zaongo, Farooq Rashid, Muhammad Suleman, Vijay Harypursat, Fangzhou Song, Yaokai Chen","doi":"10.1080/07391102.2025.2500682","DOIUrl":"https://doi.org/10.1080/07391102.2025.2500682","url":null,"abstract":"<p><p>Human P-selectin glycoprotein ligand 1 (PSGL-1) and HIV-1 viral protein U (Vpu) play major roles in limiting and increasing the ability of HIV-1 to infect cells, respectively. There is currently no published data reporting on the specific interactions between PSGL-1 and Vpu, and possible outcomes and consequences of these interactions. To date, it has only been established that Vpu binds human PSGL-1 to degrade PSGL-1 and therefore promote HIV replication. There are, however, four different types of HIV-1, and it would be helpful to know how VpuM, VpuN, VpuO, and VpuP can bind to and possibly inhibit PSGL-1 expression. Bioinformatics methods were used to find out how strongly each type of Vpu found in the different HIV-1 groups bonds with human PSGL-1. Thus, we used molecular docking (MD) and molecular dynamics simulations (MDS) to figure out how PSGL-1 and VpuM, VpuN, VpuO, and VpuP interact with each other. To ensure the reliability of the predicted outcomes, the binding energy of each model was calculated using the MM/GBSA technique. Our findings show that PSGL-1-VpuP (4 H bonds, 2 salt bridges) and PSGL-1-VpuM (3 H bonds, 2 salt bridges) have stronger bonding affinities than PSGL-1-VpuN (4 H bonds, no salt bridges) and PSGL-1-VpuO (2 H bonds, 1 salt bridge). The MDS test also shows that PSGL-1-VpuM and PSGL-1-VpuP protein complexes are more stable and compact, with lower residual fluctuations compared to PSGL-1-VpuN and PSGL-1-VpuO protein complexes. Binding free energies of -82.27 ± 1.35 kcal/mol, -82.17 ± 0.84 kcal/mol, -67.84 ± 0.63 kcal/mol, and -131.86 ± 1.08 kcal/mol were recorded for each of PSGL1-VpuM, PSGL1-VpuN, PSGL1-VpuO, and PSGL1-VpuP, respectively, which further supports our results. Our research shows that Vpu from the M and P HIV-1 groups may be better at blocking human PSGL-1 than VpuO and VpuN groups. These results are novel in this specific realm of HIV research, and as such, further investigations in more robust experimental studies are warranted.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-11"},"PeriodicalIF":2.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019399","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":"Bioinformatics approach reveals the modulatory role of JUN in atorvastatin-mediated anti-breast cancer effects.","authors":"Mohamed Y Foda, Sara A Al-Shun, Guendouzi Abdelkrim, Mohamed L Salem, Nevin A Salah, Omali Y El-Khawaga","doi":"10.1080/07391102.2025.2499950","DOIUrl":"https://doi.org/10.1080/07391102.2025.2499950","url":null,"abstract":"<p><p>Atorvastatin, a widely prescribed cholesterol-lowering drug, has recently shown potential anticancer effects. However, its influence on gene expression and its biological functions in cancer, in particular breast cancer, still unclear. We aim to identify the dysregulated genes associated with atorvastatin treatment and the main players in their biological network. A total of 103 differentially expressed genes (DEGs) in the unified signature were identified, and the functional enrichment analysis suggested their relation to multiple cancer-related pathways. JUN was identified as the hub gene in the protein-protein interaction (PPI) network and was shown to be responsive to atorvastatin in breast cancer. Atorvastatin exhibited notable predicted cytotoxicity against breast cancer lines, with the activity positively correlated with JUN expression. JUN was significantly downregulated in breast cancer expression inversely correlated with cancer progression, whereas higher JUN expression was linked with better survival outcomes. Atorvastatin may directly interact with JUN protein forming a more compact and stable conformation. These findings demystify the potential therapeutic mechanism of atorvastatin in breast cancer, possibly by fine tuning of JUN expression. As such, JUN might serve as a valuable prognostic biomarker in breast cancer.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-21"},"PeriodicalIF":2.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986155","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":"Microscopic effects of proline co-solvent on alanine homopeptide structure, solvation and helix folding dynamics.","authors":"Krzysztof Kuczera, Robert Szoszkiewicz, Gouri S Jas","doi":"10.1080/07391102.2025.2500681","DOIUrl":"https://doi.org/10.1080/07391102.2025.2500681","url":null,"abstract":"<p><p>We present a computational investigation to explore the influence of the protective osmolyte proline as a co-solvent on peptide structure and dynamics for a series of alanine-based peptides, (ALA)n of length <i>n</i> = 5, 8, 15, and 21 residues. Applying multi-microsecond molecular dynamics simulations in a 2 M proline solution, we evaluate peptide structure, solvation and helix folding dynamics and compare to behavior in pure water. Proline addition enhances helix content and significantly slows folding and unfolding times, correlating with a 1.9-fold increase in solvent viscosity. Notably, ALA15 helix content increases from 25% to 49% and relaxation time rises from 110 ns to 540 ns in proline relative to water. Microscopic solvation effects of proline include peptide compaction and dehydration, exclusion of proline from the backbone, formation of weak interactions with the ALA methyl sidechains, and strong interactions with water. The differences of these effects on the helix and coil states drive helix stabilization by proline. Low-dimensional kinetic modeling with Optimal Dimensionality Reduction predicts distinct folding mechanisms: shorter peptides (ALA5-ALA15) exhibit direct helix-coil transitions, and only the longest ALA21 follows a more complex folding pathway involving intermediates. Statistically, enhanced stability of hydrogen bonds in the peptide centers and strong correlation between transitions on neighboring residues are shared between water and proline solutions. However, there is a preference for helix initiation at the N-terminus under proline influence. Our analysis describes the molecular mechanisms of how proline modulates peptide behavior, offering atomistic insights into helix stabilization and folding mechanisms mediated by osmolytes.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-11"},"PeriodicalIF":2.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019855","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":"Immunoinformatic approach for designing a multi-epitope vaccine against non-typhoidal salmonellosis using starvation-stress response proteins from <i>Salmonella</i> Oranienburg.","authors":"Lennin Isaac Garrido-Palazuelos, Mamuna Mukhtar, Salman Ali Khan, José Andrés Medrano-Félix, Haris Ahmed-Khan, Fahad M Alshabrmi, Osvaldo López-Cuevas, Berenice González-Torres, Nohelia Castro-Del Campo, Cristóbal Chaidez, José Roberto Aguirre-Sánchez, Hailah M Almohaimeed","doi":"10.1080/07391102.2025.2500685","DOIUrl":"https://doi.org/10.1080/07391102.2025.2500685","url":null,"abstract":"<p><p>Non-typhoidal <i>Salmonella</i> is responsible for gastrointestinal illnesses worldwide. Therefore, it is important to implement effective therapeutic interventions for preventing these diseases. Vaccines have proven highly efficacious in the treatment and prevention of several illnesses. Nevertheless, there is currently no authorized vaccine available for non-typhoidal salmonellosis. This study aimed to employ in silico techniques to develop a multi-epitope vaccine targeting non-typhoidal salmonellosis. Specifically, we focused on proteins associated with the starvation stress response (SSR) in <i>Salmonella</i> Oranienburg. The presence of these proteins is essential for the survival and disease of the host organism. The vaccine sequence was constructed utilizing B-cell and T-cell epitopes. Linkers, adjuvants and PADRE sequences were used to establish connections between epitopes. The vaccine exhibited no allergenicity, toxigenicity and a significantly high antigenicity score. Docking analysis conducted between the designed vaccine and the TLR-1, TLR-2 and TLR-4 receptors demonstrated favorable interactions and the potential to activate these receptors. In addition, it was found through immunological simulation testing that the vaccine elicits a robust immune response. The use of these proteins in the construction of a multi-epitope vaccine shows potential in terms of both safety and immunogenicity.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-19"},"PeriodicalIF":2.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007368","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":"Computational exploration of <i>TITIN</i> variations: insights from whole exome sequencing and molecular dynamics simulation study.","authors":"Amrita Mukhopadhyay, Bharti Devi, Anurag T K Baidya, Manohar Lal Yadav, Rajnish Kumar, Bhagyalaxmi Mohapatra","doi":"10.1080/07391102.2025.2500683","DOIUrl":"https://doi.org/10.1080/07391102.2025.2500683","url":null,"abstract":"<p><p>Titin (TTN), the largest known human protein (∼4 MDa), is considered as a key component for sarcomere integrity and function. Mutations in the <i>TTN</i> gene play a pivotal role in the genetic underpinnings of Dilated Cardiomyopathy (DCM). In the present study, we have conducted whole exome sequencing (WES) on 15 patients (5 familial and 10 sporadic) diagnosed with idiopathic DCM and identified 88 exonic variants. Here, we also report for the first time four novel variants comprising two frame-shifts, one missense, and one stop-codon variant. These variants are predominantly located in the A-band region (39 variants) of TTN, a critical region for its mechanical stability and interaction with other sarcomeric proteins, followed by the I-band domain (33 variants), Z-disc domain (7 variants), and M-band region (9 variants). To discern the functional repercussions of these variations, we have performed several bioinformatics analyses including pathogenicity prediction, protein stability, and protein-protein docking followed by molecular dynamics (MD) simulations on both wild-type and mutant TTN fragments with their corresponding interacting partners. We reveal that variations in the A-band domain significantly alter the protein's structural dynamics, leading to decreased mechanical stability and altered protein-protein interactions. These changes are likely to disrupt sarcomere function, thereby elucidating their role in the pathogenesis of DCM.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-19"},"PeriodicalIF":2.7,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020274","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}