Stefano Costanzi , Lea G. Stahr , Giampaolo Trivellin , Constantine A. Stratakis
{"title":"Comparing models and experimental structures of the GPR101 receptor: Artificial intelligence yields highly accurate models","authors":"Stefano Costanzi , Lea G. Stahr , Giampaolo Trivellin , Constantine A. Stratakis","doi":"10.1016/j.jmgm.2025.109103","DOIUrl":"10.1016/j.jmgm.2025.109103","url":null,"abstract":"<div><div>Experimental structures solved through cryo-electron microscopy have recently been published for GPR101, a G protein-coupled receptor (GPCR) implicated in the genetic condition X-linked acrogigantism (X-LAG). Here, we compared these experimental structures with computational models that we previously published, including our internally developed homology models and third-party models generated through the AlphaFold2 and AlphaFold-Multistate artificial intelligence (AI) methods. Our analysis revealed considerable accuracy for both homology models and AI-generated models. However, it also revealed the general superiority of AI methods. Particularly noteworthy is the model generated by AlphaFold2, which captured with high fidelity various structural aspects, including the challenging second extracellular loop. Our previously published homology model of the GPR101-G<sub>s</sub> protein complex, based on the β<sub>2</sub>-adrenergic receptor, accurately predicted the binding mode of the G protein to the receptor. Moreover, this model predicted the structure of the sixth transmembrane domain (TM6) significantly more accurately than the others, including those built through AI methods, suggesting that homology modeling based on templates solved in complex with the G protein of interest might be the most reliable way of modeling this transmembrane domain. Lastly, our analysis revealed that our molecular dynamics simulations did not have a significant and consistent effect on the accuracy of the models, increasing the accuracy for some domains while decreasing it for others. This work provides insights into the relative strengths of different modeling approaches for our case study on GPR101. More broadly, when considered alongside other assessment studies, it contributes to the growing body of knowledge that can guide the modeling of GPCRs for which experimental structures are not yet available.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109103"},"PeriodicalIF":2.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212137","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":"Protein-based QM-CGMM","authors":"Yi Sun","doi":"10.1016/j.jmgm.2025.109081","DOIUrl":"10.1016/j.jmgm.2025.109081","url":null,"abstract":"<div><div>We present an approach to Coarse Grain (CG) the Molecular Mechanics (MM) region in a thermodynamically consistent approach when the region is a protein backbone. This approach is achieved, via using 4 beads on each amino acid residue to replicate the electrostatic field that it generates, followed by connecting them via a heterogeneous Elastic Network Model (heteroENM) force-field. We subsequently treat the boundary between the QM and CGMM regions using appropriate Lennard-Jones parameters. We apply this procedure to the classic Chorismate Mutase system, where the enzyme backbone in the MM region catalyzes the Claisen rearrangement in the QM region using Transition-Tempered metadynamics (TTMetaD) to obtain a converged Potential of Mean Force (PMF). The CGMM reveals a free energy barrier similar to the experimental value. This work demonstrates the potential of utilizing a CGMM forcefield to capture all-atom thermodynamic properties at a reduced cost.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109081"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212138","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-function activity study of the unusual protein MAPK1-109aa encoded by the non-coding circular RNA hsa_circ_0004872","authors":"Jit Mondal , Sima Biswas , Sreekanya Roy , Anirban Nandy , Dipanjan Guha , Angshuman Bagchi","doi":"10.1016/j.jmgm.2025.109098","DOIUrl":"10.1016/j.jmgm.2025.109098","url":null,"abstract":"<div><div>Circular RNAs are closed-loop single-stranded non-coding RNA molecules. Once considered as transcriptional junks, their physiological roles in the process of tumourigenesis have recently been being identified. In spite of belonging to the class of non-coding RNAs, some of them have distinct protein coding abilities. The circular RNA hsa_circ_0004872, which encodes the protein MAPK1–109aa, is one such example. This protein is associated with gastric cancer pathway, as, MAPK1–109aa can bind to MEK1 and inhibit the phosphorylation of MAPK1 and this further disturbs the downstream signalling and activation processes necessary for the onset of gastric cancer. However, the residue level details of the binding interactions of MAPK1-109aa and its partners are not yet available. Therefore, our aim is to delineate the structural details and folding pattern of the protein and provide insight on its mode of interactions with its binding partner, MEK1. Furthermore, we tried to determine whether MAPK1-109aa has its role in any pathway(s) other than gastric cancer. Through the technique of network analyses, we could predict that the protein is associated with the pathways that lead to conditions like neurodegenerations and others. This work is the first of its kind, which elucidates the residue-level pattern of interactions of MAPK1-109aa with MEK1 in gastric cancer onset as well as the association of MAPK1-109aa with other diseases. This work highlights the potential application of MAPK1-109aa as a therapeutic agent for the treatment of gastric cancer.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109098"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222497","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":"Manipulating high Curie temperature of Sm/Ag doped ZnO monolayers by first-principles GGA+U study","authors":"Hao Yuan , Yanfang Zhao , Yuanbin Xiao , Bing Yang , Wei Ding , Jian Lv","doi":"10.1016/j.jmgm.2025.109101","DOIUrl":"10.1016/j.jmgm.2025.109101","url":null,"abstract":"<div><div>This work studies the electronic structure, and magnetic properties of Sm/Ag doped ZnO monolayer by first-principles GGA + U calculations. The results show Sm-doped ZnO monolayer exhibits stable room temperature ferromagnetism with a high magnetic moment of 5.91 μB per unit. The total magnetic moment of the system is mainly contributed by Sm-4f, and the high Curie temperature results from the strong ferromagnetic coupling between the adjacent Sm atoms. The Ag-doped ZnO monolayers undergo magnetic quenching with the Ag doping concentration from 6.25 at.% to 12.5 at.%, which is extremely advantageous for designing and manufacturing magnetic switches. The ZnO monolayer shifts between the non-magnetic to the antiferromagnetic as the distance between neighboring two Ag atoms changes. In Sm-Ag co-doped ZnO monolayer, the Sm atom and Ag atom spin in opposite directions, and the magnetic moments partially cancel out, and the total magnetic moment of the system decreases. In addition, Sm/Ag mono-doped and Sm-Ag co-doped ZnO monolayer exhibited half-metallic behavior due to the impurity energy levels introduced in the bandgap by Sm/Ag dopant, and calculations of the formation energy show that dopants are prone to aggregate. This research may provide a reference for modifying the material properties of ZnO monolayers and designing nano-electronic and spintronic devices.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109101"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204613","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}
Alessia Bono , Gabriele La Monica , Federica Alamia , Francesco Mingoia , Annamaria Martorana , Antonino Lauria
{"title":"Combinatorial chemistry-driven In silico design and computational evaluation of covalent peptidomimetic SARS-CoV-2 main protease inhibitors via structure-based virtual screening and multivariate analysis","authors":"Alessia Bono , Gabriele La Monica , Federica Alamia , Francesco Mingoia , Annamaria Martorana , Antonino Lauria","doi":"10.1016/j.jmgm.2025.109100","DOIUrl":"10.1016/j.jmgm.2025.109100","url":null,"abstract":"<div><div>The COVID-19 pandemic has underscored the urgent need for specific pharmacological treatments beyond existing vaccines. One of the most attractive targets for antiviral therapies development is the SARS-CoV-2 Main Protease (M<sup>PRO</sup>), a key enzyme in viral life. The lack of M<sup>PRO</sup> human homologs and its conservation rate among coronaviruses make this enzyme strategically important. Considering its mechanism of action, the catalytic cysteine residue (Cys<sup>145</sup>) presents a prime target for covalent inhibition. Electrophilic warhead inhibitors, designed to react with this catalytic site, mimic the amide peptide bonds of the viral polyproteins, thereby facilitating their binding and subsequent inactivation of the enzyme. Their activity is further potentiated when incorporated into peptidomimetic structures. <em>In silico</em> approaches are gaining increasing importance in the search for effective COVID-19 treatments. In this view, this study focuses on developing an innovative <em>in silico</em> protocol for identifying anti-SARS-CoV-2 agents covalently targeting M<sup>PRO</sup>. To this purpose, a combinatorial library of 450 peptidomimetic compounds with aldehydic warheads was generated, refined to 388 compounds through docking studies, and further evaluated for covalent binding capabilities, revealing that compounds <strong>9</strong>–<strong>14</strong>, <strong>16</strong>, and <strong>20</strong> exhibited significantly higher affinities compared to known inhibitors, even during a 200 ns dynamics simulation, thus affirming the validity of the adopted design strategy. Furthermore, this work takes the advantages of our in-house ligand-based tool, the Biotarget Predictor Tool, available in DRUDIT, integrated with both structure-based techniques and, interestingly, multivariate statistical analysis.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109100"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196115","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}
Hongjiang Ren , Panpan Wang , Gang Zhu , Liuchang Wang , Gang Wang , Yaping He
{"title":"A new insight of structures, bonding and electronic properties for 6-mercaptopurine adsorbed on M@Au12 (M=Au, Ag, Pd and Pt) Nanoclusters: a theoretical perspective","authors":"Hongjiang Ren , Panpan Wang , Gang Zhu , Liuchang Wang , Gang Wang , Yaping He","doi":"10.1016/j.jmgm.2025.109097","DOIUrl":"10.1016/j.jmgm.2025.109097","url":null,"abstract":"<div><div>The metal complexes M@Au<sub>12</sub>-6MP (M = Au, Ag, Pd and Pt) have been investigated theoretically using B3LYP//6–311++G (d, p) and M06-L//def2-TZVP methods. The electronic and energy properties were analyzed. The results show that either in the gas phase or aqueous phase, the stability of four complexes for the tautomer 6MP-7 with metal clusters is higher than that of 6MP-9. The adsorption energy <em>E</em><sub>ad</sub> including BSSE for Pt@Au<sub>12</sub>-6MP-7 is the lowest with −1.41eV in the gas phase and that for Pd@Au<sub>12</sub>-6MP-7 is the lowest with −1.12 eV in the aqueous phase. The electronic property, molecular orbital analysis, density of states, the second order perturbation energy in NBO explicit that Pt@Au<sub>12</sub>-6MP-7 and Pd@Au<sub>12</sub>-6MP-7 are better potential candidate for 6 MP drug delivery.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109097"},"PeriodicalIF":2.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204612","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":"Unveiling the chlorinated aliphatic hydrocarbon contaminants sensing properties of the biphenylene network through DFT calculations","authors":"Erwin García-Hernández","doi":"10.1016/j.jmgm.2025.109099","DOIUrl":"10.1016/j.jmgm.2025.109099","url":null,"abstract":"<div><div>Biphenylene, a recently synthesized graphene allotrope, has demonstrated potential for pollutant adsorption and sensing applications. In this study, we investigate the interactions between biphenylene and three chlorinated aliphatic hydrocarbons: dichloroethylene, trichloromethane, and tetrachloroethylene, utilizing density functional theory calculations. Geometrical analysis shows that all complexes exhibit interaction distances above 3.3 Å, indicating physisorption governed by van der Waals forces. The complex with tetrachloroethylene exhibits the strongest interaction (adsorption energy of −0.48 eV) due to π–π stacking, while the systems with trichloromethane and dichloroethylene exhibit weaker adsorption (−0.30 eV and −0.35 eV, respectively). Solvent effects slightly diminish adsorption stability by up to ∼6 %. Electronic analysis reveals that biphenylene retains its intrinsic properties upon complexation, with minimal changes in the HOMO-LUMO gap (1.00 eV) and chemical potential (−3.92 eV). However, the dipole moment increases significantly (up to 1.40 D for the trichloromethane complex), enhancing solubility. Rapid recovery times for the complexes with trichloromethane (1.33 × 10<sup>−7</sup> s) and dichloroethylene (8.41 × 10<sup>−7</sup> s) suggest excellent sensing capabilities, while the tetrachloroethylene system's longer desorption time (1.42 × 10<sup>−4</sup> s) indicates potential for pollutant adsorption. These findings highlight biphenylene as a promising material for environmental applications, including the sensing and removal of chlorinated pollutants.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109099"},"PeriodicalIF":2.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189547","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}
Khalida Abaid Samawi , Shaimaa Imad Ali , Taghried A. Salman , Belal A. Alshekhly
{"title":"Exploring the capabilities of metal-doped phthalocyanine (MPC, M = Co, Cu, Fe, Ni, Zn) for adsorption of CO2: A DFT study","authors":"Khalida Abaid Samawi , Shaimaa Imad Ali , Taghried A. Salman , Belal A. Alshekhly","doi":"10.1016/j.jmgm.2025.109088","DOIUrl":"10.1016/j.jmgm.2025.109088","url":null,"abstract":"<div><div>Phthalocyanine-based covalent organic frameworks (PC-COFs) are a novel subclass of COFs that integrate phthalocyanine units to enhance electronic, optical, and catalytic properties. These frameworks are particularly effective in CO<sub>2</sub> adsorption due to their high surface area, tunable porosity, and exceptional stability. In this study, we have employed density functional theory (DFT) calculations to explore the electronic properties of phthalocyanine doped with various metal centers (Co, Cu, Fe, Ni, Zn) and their impact on CO<sub>2</sub> adsorption. The geometries of metal-doped phthalocyanines and their CO<sub>2</sub> complexes were optimized using the B3PW91 functional with the LANL2DZ basis set. Adsorption energies, electronic structures, and reactivity indices such as HOMO-LUMO gaps, ionization potentials, and electron affinities were analyzed. The findings revealed that Fe-doped phthalocyanines exhibited the highest reactivity and strongest CO<sub>2</sub> adsorption due to favorable charge transfer interactions. Additionally, aromaticity indices (HOMA and Bird) indicated enhanced aromatic character upon CO<sub>2</sub> adsorption. These insights provide a foundation for designing more efficient PC-COF materials for CO<sub>2</sub> capture, emphasizing the crucial role of electronic properties and metal center selection in optimizing adsorption performance.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109088"},"PeriodicalIF":2.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168064","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}
Tianhao Li , Fang Chen , Guoqi Guo , Ling Dong , Xiaofeng Yuan , Linxiu Zhao , Duanlin Cao
{"title":"Thermal decomposition mechanism of HMX/DNAN at high temperatures by reactive molecular dynamics simulations","authors":"Tianhao Li , Fang Chen , Guoqi Guo , Ling Dong , Xiaofeng Yuan , Linxiu Zhao , Duanlin Cao","doi":"10.1016/j.jmgm.2025.109096","DOIUrl":"10.1016/j.jmgm.2025.109096","url":null,"abstract":"<div><div>This work investigated the thermal decomposition process of the HMX/DNAN melt-cast explosive system at high temperatures using reactive molecular dynamics. The initial reaction paths of the system and the effects of DNAN on the thermal decomposition of HMX were revealed. The findings indicated that the H atoms and nitro groups produced by the decomposition of DNAN were reacted with HMX and its intermediates, which in turn promoted the pyrolysis of HMX, while the OH radicals produced by the decomposition of HNO<sub>2</sub> continued to induce the decomposition of HMX. Calculations of activation energies showed that the addition of DNAN enhanced the sensitivity of HMX to thermal stimuli. In terms of products, the addition of DNAN significantly impacted the final product H<sub>2</sub>O of HMX, while its impact on CO<sub>2</sub> is relatively small. At 2000 K–3500 K, the maximum number of clusters in mixed system showed a general decreased trend with increased temperature.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109096"},"PeriodicalIF":2.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168062","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":"Effect of isomerism, inter-ring torsion angle and chain length in structural and electronic properties of oligothiophenes: computational study","authors":"Belgacem Bezzina , Safia Himri , Mohamed Tayeb Abedghars , Assia khelalfa , Djameleddine Khatmi","doi":"10.1016/j.jmgm.2025.109085","DOIUrl":"10.1016/j.jmgm.2025.109085","url":null,"abstract":"<div><div>Density Functional Theory (DFT) and Time-Dependent DFT (TD-DFT) methods are employed to investigate the influence of isomerism and inter-ring torsion angle on the energetic, electronic, and structural properties of bithiophenes. Furthermore, the effect of the chain length of polythiophene (1–24 units) on their structural and electronic properties has been established.</div><div>The anti-gauche rotamer represents the most energetically favorable and reactive conformation in 2,2′-bithiophene, while the syn-gauche is the less stable rotamer in 3,3′-bithiophene. The inter-ring torsion energy profile for 2,2′-bithiophene reveals that the most stable conformer is twisted, exhibiting an optimized dihedral angle of 146.27° and a rotational barrier of approximately 1.48 kcal/mol. Increasing the length of the thiophene chain from one to 24 rings induces significant changes in their structural and electronic properties. The curvature behavior of oligothiophenes decreases as the oligomer size increases, from 0.0359 Å<sup>−1</sup> for T2 to 0.0270 Å<sup>−1</sup> for T24. The maximum absorption wavelengths of the oligothiophenes are red-shifted from 216.26 nm for T1 to 527.96 nm for T24. The orbital and optical band gaps of these oligothiophenes were calculated and plotted against 1/Tn. Linear relationships were obtained in both cases, with the optical band gap showing better agreement with experimental data. The extrapolated energy gap for infinitely long polythiophene is 2.15 eV in chloroform and 2.20 eV in the gas phase, consistent with the experimental values of 2.0–2.20 eV.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109085"},"PeriodicalIF":2.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124233","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}