Journal of molecular graphics & modelling最新文献

{"title":"Unravelling selectivity discrepancies of protoporphyrin binding to glutathione transferase: A comparative analysis of molecular dynamic simulated versus implicit solvent-minimized protein models","authors":"Neo Padi ,&nbsp;Sadhna Mathura ,&nbsp;Ikechukwu Achilonu","doi":"10.1016/j.jmgm.2025.108971","DOIUrl":"10.1016/j.jmgm.2025.108971","url":null,"abstract":"<div><div>Schistosomiasis is a neglected tropical disease caused by parasitic trematodes, which are an ongoing global health and veterinary concern owing to their acquired drug resistance pressure to available treatment. There is a need for a new generation of effective anthelmintics for preventive and therapeutic purposes. Natural products, such as porphyrins, have been reported to inhibit the main detoxification enzymes in these parasites, called glutathione transferases, which help them evade immune response and drug therapy, thus making them good drug targets. Computational modelling was used to screen potential inhibitors out of 461 protoporphyrin IX-like compounds, including a potent known inhibitor called bromosulfophthalein. However, unlike traditional docking, where the stable energy-minimized structure is used, a short molecular dynamic simulation step was added to yield the most averaged protein structure conformation as the starting point of high throughput virtual screening. Here, it was shown that the starting point is crucial as the results suggested different lead compounds; for the 26-kDa <em>japonicum</em> GST, the top-scoring compounds were CID: 122690402 for the minimized structure and CID: 137797052 for the MD-simulated structure. Similarly, for the 28-kDa <em>haematobium</em> GST, the lead compounds were CID: 70415734 and CID: 69301914, respectively. These results highlight the importance of incorporating protein dynamics into structure-based drug design and provide valuable insights into the development of porphyrin-based therapeutics against schistosomiasis and other helminthic infections.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108971"},"PeriodicalIF":2.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fosamprenavir and Tirofiban to combat COPD and cancer: A drug repurposing strategy integrating virtual screening, MD simulation, and DFT studies","authors":"Jigme Sangay Dorjay Tamang ,&nbsp;Suvankar Banerjee ,&nbsp;Balaram Ghosh ,&nbsp;Nilanjan Adhikari","doi":"10.1016/j.jmgm.2025.108967","DOIUrl":"10.1016/j.jmgm.2025.108967","url":null,"abstract":"<div><div>Matrix metalloproteinases (MMPs) are involved in different pathophysiological conditions like cancer, COPD, asthma, and inflammatory diseases. Among these MMPs, macrophage metalloelastase is one of the prime targets for COPD, and cancer. Therefore, to combat such diseases, potent novel macrophage metalloelastase inhibitors can be considered. Here, the classification-based molecular modeling was performed on large data of macrophage metalloelastase inhibitors that identified dibenzofuran, and diphenyl ether groups as important substructures contributing towards potent macrophage metalloelastase inhibition. This information was further implicated in repurposing marketed drugs through fragment-based and molecular docking-based virtual screening with molecular dynamics (MD) simulation-based stability validation and DFT calculations. This study identified fosamprenavir and tirofiban as promising hits that can exhibit potent macrophage metalloelastase inhibition which was also validated by the MD simulation and DFT-based calculations. Therefore, this study not only revealed these repurposed drugs as effective macrophage metalloelastase inhibitors but also opened up a horizon in developing novel potent macrophage metalloelastase inhibitors for the management of cancer and COPD in the future.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108967"},"PeriodicalIF":2.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based analysis of missense mutations impacting the catalytic and substrate binding sites of hRPE65","authors":"Giulio Poli,&nbsp;Marco Macchia,&nbsp;Tiziano Tuccinardi","doi":"10.1016/j.jmgm.2025.108963","DOIUrl":"10.1016/j.jmgm.2025.108963","url":null,"abstract":"<div><div><em>h</em>RPE65 is a critical enzyme in the retinoid visual cycle and is implicated in retinal diseases caused by missense mutations that affect its function. However, many <em>h</em>RPE65 variants of uncertain significance (VUS) remain unclassified, hindering their clinical interpretation. This study aims to develop a molecular dynamics (MD)-based protocol to evaluate the pathogenicity of missense mutations located within the catalytic and substrate pockets of <em>h</em>RPE65. Using a full-length <em>h</em>RPE65 model complexed with all-<em>trans</em>-retinylpalmitate, we assessed 15 VUS for their structural and functional impacts. Our findings provide insights into the deleterious effects of these mutations, offering a framework for reclassifying VUS and identifying patients eligible for gene therapy. This approach may support clinicians in improving diagnostic precision and therapeutic decision-making for retinal diseases.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108963"},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitory mechanism of lithospermic acid on the fibrillation of type 2 diabetes associated islet amyloid polypeptide","authors":"Anisha Manchanda,&nbsp;Bhupesh Goyal","doi":"10.1016/j.jmgm.2025.108972","DOIUrl":"10.1016/j.jmgm.2025.108972","url":null,"abstract":"<div><div>The abnormal fibrillation of a 37-residue peptide hormone human islet amyloid polypeptide (hIAPP) is linked with type 2 diabetes (T2D). Pang et al. depicted a prominent role of lithospermic acid (LA) in blocking hIAPP fibrillation and alleviating the hIAPP aggregates-induced cytotoxicity. LA is a polyphenolic compound present in extra virgin olive oil with therapeutic properties. Despite its notable inhibitory effect on hIAPP fibrillation, the inhibition mechanism remains unclear. Here, molecular dynamics (MD) simulations have been utilized to shed light on the putative binding mechanism and inhibitory mechanism of LA against hIAPP fibrillation. The molecular docking predicted favourable binding (−7.1 kcal/mol) of LA with hIAPP. Interestingly, LA increases the helix content in hIAPP and blocks the conformational transition to the aggregation-competent conformations. The conformational clustering and hydrogen bond analyses depicted that LA formed hydrogen bonds with Asn21 of hIAPP, which play an important role in hIAPP aggregation. LA binds favourably to hIAPP (Δ<em>G</em>_binding = −49.62 ± 3.34 kcal/mol) with a major contribution from the van der Waals interactions. The MD simulations highlighted that LA dramatically interfered with the intrapeptide interactions and inhibited sampling of aggregation-competent β-sheet conformations in hIAPP <em>via</em> hydrogen bonds through its hydroxyl groups, van der Waals interactions with hIAPP residues, thus blocking hIAPP aggregation to β-sheet rich cytotoxic fibrillar aggregates. The MD simulations illuminated specific interactions between hIAPP and LA, which will benefit in developing new chemical entities against hIAPP fibrillation.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108972"},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143216288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel microsomal prostaglandin E2 synthase 1 (mPGES-1) inhibitors by a structurally inspired virtual screening study","authors":"Abdurrahman Olğaç ,&nbsp;Paul M. Jordan ,&nbsp;Christian Kretzer ,&nbsp;Oliver Werz ,&nbsp;Erden Banoglu","doi":"10.1016/j.jmgm.2025.108962","DOIUrl":"10.1016/j.jmgm.2025.108962","url":null,"abstract":"<div><div>Prostaglandin (PG) E₂ is a pro-inflammatory lipid mediator derived from the metabolism of arachidonic acid (AA) by cyclooxygenases (COX) and PGE₂ synthases. Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly used in the treatment of inflammation, nonselectively inhibit COX activity and decrease PGE₂ production. However, these drugs cause gastrointestinal bleeding and several cardiovascular complications. Therefore, inhibiting microsomal PGE₂ Synthase-1 (mPGES-1) to block PGE₂ production downstream of COX is expected to yield safer and more effective treatments for inflammation, cancer, and cardiovascular diseases. At present, there are no mPGES-1 inhibitors available on the market, but ongoing research continuously evaluates new compounds in both preclinical and clinical stages. Here, we conducted a high throughput virtual screening campaign to discover novel mPGES-1 inhibitor scaffolds. This campaign utilized physicochemical filtering alongside both structure-aware ligand-based approaches (shape screening templates and pharmacophore models, which were generated based on the 3D binding modes of the co-crystallized mPGES-1 inhibitors) and structure-based strategies (refinement with docking and molecular dynamics). Thirty-four compounds were selected and biologically tested for mPGES-1 inhibition in a cell-free assay using microsomes from interleukin-1β-stimulated A549 cells as the source of mPGES-1. The most potent compound inhibited the remaining enzyme activity with an IC₅₀ value of 6.46 μM in a cell-free assay for PGE₂ production. We also compared the binding patterns of the most active compounds identified in this study with those of co-crystallized inhibitors using molecular dynamics simulations. This comparison underscored the crucial role of ionic interactions, π-π interactions, hydrogen bonds, and water bridges involving specific amino acids. Our results highlight the importance of these interaction networks within the binding cavity in various binding scenarios. Ultimately, the insights gained from this study could assist in designing and developing new mPGES-1 inhibitors.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108962"},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico molecular characterization of a cyanobacterial lytic polysaccharide monooxygenase","authors":"Rodrigo Virgolino ,&nbsp;Andrei Siqueira ,&nbsp;Juliana Cassoli ,&nbsp;Délia Aguiar ,&nbsp;Evonnildo Gonçalves","doi":"10.1016/j.jmgm.2025.108970","DOIUrl":"10.1016/j.jmgm.2025.108970","url":null,"abstract":"<div><div>Lytic polysaccharide monooxygenases (LPMOs) are copper-dependent enzymes that catalyze the oxidative cleavage of β(1–4) glycosidic bonds and have attracted considerable attention because of their potential for enhancing efficiency in degrading recalcitrant polymeric substrates, in synergism with hydrolytic enzymes. Fungal-derived LPMOs are the most prevalent type, while other taxonomic groups have been described as potential alternative sources of these enzymes. In the present study, we aimed to identify and characterize <em>in silico</em> a LPMO of cyanobacterial origin with putative functions in chitin depolymerization. A similarity search of sequences and conservation of domains with characterized LPMOs identified a 289 amino acid protein from the cyanobacterium <em>Mastigocoleus testarum</em> (Order Nostocales), likely belonging to the CAZy-AA10 class. This protein is referred to as <em>Mt</em>LPMO10. Phylogenetic analysis revealed that <em>Mt</em>LPMO10 is homologous to the protein Tma12 from the fern <em>Tectaria macrodonta</em>, with 52.11 % sequence identity, which was the first LPMO characterized as originating from the plant kingdom. The protein tertiary structure predicted by the AlphaFold server indicates structural features common to LPMOs, such as a histidine brace formed by His31 and His132 and an immunoglobulin-like domain composed of antiparallel beta strands. Molecular dynamics (MD) simulation allowed the assessment of the enzyme-substrate affinity, using an initial pose based on literature data. The <em>Mt</em>LPMO10-chitin complex remained stable during 100ns of MD, while the <em>Mt</em>LPMO10-cellulose complex dissociated within 30ns of MD. Additionally, there was a shorter Cu(I)-H4 distance in the protein-substrate complex compared to the Cu(I)-H1 distance (averages of 6.0 ± 0.7 Å and 7.9 ± 0.7 Å, respectively), suggesting a C4 regioselectivity. This study highlights the existence of lytic polysaccharide monooxygenases in cyanobacteria and paves the way for further investigations related to this enigmatic class of enzymes and their potential use in biotechnological applications.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108970"},"PeriodicalIF":2.7,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143149858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 electronic structure, mechanical stability and optoelectronic responses of arsenic-based M2AsX (M = Nb, Mo and X = C, N) MAX phase ceramics","authors":"Mubashar Ali ,&nbsp;Zunaira Bibi ,&nbsp;Tehreem Fatima ,&nbsp;Shamsa Kanwal ,&nbsp;Houbing Huang ,&nbsp;Bakar Bin Khatab Abbasi ,&nbsp;Munirah D. Albaqami","doi":"10.1016/j.jmgm.2025.108965","DOIUrl":"10.1016/j.jmgm.2025.108965","url":null,"abstract":"<div><div>This study utilizes first-principles computations to examine the electronic structure, mechanical stability, and optoelectronic responses of arsenic-based <span><math><mrow><msub><mi>M</mi><mn>2</mn></msub><mtext>AsX</mtext></mrow></math></span> (M = Nb, Mo and X = C, N) ceramics. We assessed the stability of these compounds by calculating their formation enthalpies and phonon dispersion curves, which showed that all the compounds we examined are stable and can be synthesized successfully. The robustness of these materials was also analyzed using elastic constants, which further confirmed that the <span><math><mrow><msub><mi>M</mi><mn>2</mn></msub><mtext>AsX</mtext></mrow></math></span> phases are stable and not prone to mechanical instability. Furthermore, the ductility or brittleness of the studied <span><math><mrow><msub><mi>M</mi><mn>2</mn></msub><mtext>AsX</mtext></mrow></math></span> compounds have been assessed by some other mechanical parameters such as Pughs and Poisson ratio, Cauchy pressure, and anisotropy factors. The acquired band structures and density of states demonstrate the metallic nature of all <span><math><mrow><msub><mi>M</mi><mn>2</mn></msub><mtext>AsX</mtext></mrow></math></span> compounds. Additionally, we have explored the several optical attributes <span><math><mrow><msub><mi>M</mi><mn>2</mn></msub><mtext>AsX</mtext></mrow></math></span> compounds in order to understand how these compounds interact with incoming electromagnetic radiation. The remarkable features of <span><math><mrow><msub><mi>M</mi><mn>2</mn></msub><mtext>AsX</mtext></mrow></math></span> compounds are expected to render them suitable for a range of applications.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108965"},"PeriodicalIF":2.7,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular insight into transport properties of Troger's base based polyimide membrane","authors":"Feng Gu ,&nbsp;Yunqin Xiao ,&nbsp;Wenxiu Zou ,&nbsp;Shenshen Li ,&nbsp;Zhaohui Wang ,&nbsp;Qinghua Wang ,&nbsp;Jijun Xiao","doi":"10.1016/j.jmgm.2025.108966","DOIUrl":"10.1016/j.jmgm.2025.108966","url":null,"abstract":"<div><div>Molecular Dynamics (MD) simulations were employed to investigate the transport properties of three polyimides comprising various diamines and dianhydrides. The diamines were 2,8-diamine-4,10-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (TB1) and 3,9-diamine-4,10-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (TB2); the dianhydrides were 4,4’-(hexafluoroisopropylidene) diphthalic anhydride (6FDA) and 4,4′-oxydiphthalic anhydride (ODPA). And the three polyimides were denoted as p-TB1-6FDA, p-TB1-ODPA and p-TB2-6FDA, respectively. The simulations provided the properties of the bulk polyimides such as glass transition temperature, fractional free volume, and solubility parameter. The results obtained were generally in consistent with experimental findings, which validated the quality of the model construction. Diffusion coefficient of carbon dioxide (CO₂) in polyimide membrane was extracted based on mean square displacement analysis. Further research on backbone dihedral distribution and radial distribution function unveiled that Troger (TB1 or TB2) bases exerted strong influence on intra-chain mobility, 6FDA components were evenly distributed in polyimide matrix thus inhibiting inter-chain packing and CO₂ molecules in free volume are surrounded by layers formed by Oxygen/Nitrogen atoms.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108966"},"PeriodicalIF":2.7,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143149856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 effect of Zr/B ratio on the stability and reactivity of activated ε-caprolactone complexes: A DFT, QTAIM and NCI study","authors":"Wijitra Meelua ,&nbsp;Tanchanok Wanjai ,&nbsp;Jitrayut Jitonnom","doi":"10.1016/j.jmgm.2025.108960","DOIUrl":"10.1016/j.jmgm.2025.108960","url":null,"abstract":"<div><div>Monomer insertion, leading to the formation of an activated monomer complex, is a critical step in cationic ring-opening polymerization (CROP) of cyclic monomers, such as ε-caprolactone (CL). In this study, Density Functional Theory (DFT) calculations were employed to investigate the structural and electronic properties of four activated complexes at two Zr:B ratios (1:2 and 1:1), where Zr is the cationic zirconocene catalyst, Cp₂ZrMe⁺, and B is the borate cocatalyst, [MeB(C₆F₅)₃]^‒ or [B(C₆F₅)₄]^‒. Steric hindrance at the reactive site was analyzed using topographic steric maps, while inter- and intramolecular interactions of the complex systems were examined through the Quantum Theory of Atoms in Molecules (QTAIM) and non-covalent interaction (NCI) analyses. The 1:2 ratio exhibited significant steric hindrance above and below the monomer plane, restricting access to the Cp₂ZrMe⁺ catalytic site and potentially limiting monomer insertion. In contrast, the 1:1 ratio displayed reduced steric congestion and stronger localized attractive forces at the catalytic site, facilitating better interactions with monomers and solvents. Conceptual DFT descriptors revealed that 1:1 systems had smaller HOMO-LUMO energy gaps, lower hardness, and higher electrophilicity, with 1:1@[B(C₆F₅)₄]⁻ identified as the most reactive complex. QTAIM identified key hydrogen bonding interactions, and the Zr-O_CL bonds, distinguishing stability and reactivity across Zr:B ratios. These findings provide valuable insights into the steric and electronic effects on monomer-activated species, enabling the optimization of Zr:B ratios and cocatalyst conditions for improved polymerization efficiency.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108960"},"PeriodicalIF":2.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the impact of S-adenosylmethionine and histamine binding on N-methyltransferase conformational dynamics: Insights from an in silico study","authors":"Qi Chu ,&nbsp;Shuyang Sun ,&nbsp;Congcong Li ,&nbsp;Ge Qu ,&nbsp;Zhoutong Sun","doi":"10.1016/j.jmgm.2025.108961","DOIUrl":"10.1016/j.jmgm.2025.108961","url":null,"abstract":"<div><div>S-adenosylmethionine (SAM)-dependent histamine N-methyltransferase (HNMT) is a crucial enzyme involved in histamine methylation, playing an important role in the epigenetic modification of biology. It entails the addition of methyl groups to histamine molecules, thereby regulating gene expression, cellular signal transduction, and other biological processes. Therefore, gaining a profound understanding of the detailed mechanism underlying HNMT-mediated methylation reactions is instrumental in elucidating the role of histamine methylation in biology. This study employed molecular dynamics (MD) simulations to assess the mechanism of cooperative catalytic reaction between the substrate-binding domain (S domain) and the cofactor-binding domain (C domain) of HNMT. The results indicated that the interplay between the cofactor (SAM) and the C domain was mostly unaltered by substrate Histamine (HSM) binding. Nevertheless, SAM binding could induce conformational changes in the S domain, thus creating a favorable environment for substrate recognition and catalysis. Additionally, key amino acid residues that significantly contributed to substrate binding were identified based on molecular mechanics-generalized Born surface area (MM/GBSA) calculations. These findings could serve as a theoretical basis for the design of potential inhibitors and modulators targeting HNMT.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"136 ","pages":"Article 108961"},"PeriodicalIF":2.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}