Journal of molecular graphics & modelling最新文献

Engineering affinity of humanized ScFv targeting CD147 antibody: A combined approach of mCSM-AB2 and molecular dynamics simulations 人源化 ScFv 靶向 CD147 抗体的亲和力工程：mCSM-AB2 与分子动力学模拟相结合的方法

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-13 DOI: 10.1016/j.jmgm.2024.108884

{"title":"Engineering affinity of humanized ScFv targeting CD147 antibody: A combined approach of mCSM-AB2 and molecular dynamics simulations","authors":"","doi":"10.1016/j.jmgm.2024.108884","DOIUrl":"10.1016/j.jmgm.2024.108884","url":null,"abstract":"<div><div>This study aims to assess the effectiveness of mCSM-AB2, a graph-based signature machine learning method, for affinity engineering of the humanized single-chain Fv anti-CD147 (HuScFvM6-1B9). In parallel, molecular dynamics (MD) simulations were used to gain valuable insights into the dynamics and affinity of the HuScFvM6-1B9-CD147 complex. The result analysis involved integrating free energy changes calculated from the mCSM-AB2 with binding free energy predictions from MD simulations. The simulated structures of the modified HuScFvM6-1B9-CD147 domain 1 complex from MD simulations were used to highlight critical residues participating in the binding surface. Interestingly, alterations in the pattern of amino acids of HuScFvM6-1B9 at the complementarity determining regions interacting with the 31EDLGS35 epitope were observed, particularly in mutants that lost binding activity. The predicted mutants of HuScFvM6-1B9 were subsequently engineered and expressed in <em>E. coli</em> for subsequent binding property validation. Compared to WT HuScFvM6-1B9, the mutant HuScFvM6-1B9<sup>L1:N32Y</sup> exhibited a 1.66-fold increase in binding affinity, with a K<sub>D</sub> of 1.75 × 10<sup>−8</sup> M. While mCSM-AB2 demonstrates insignificant improvement in predicting binding affinity enhancements, it excels at predicting negative effects, aligning well with experimental validation. In addition to binding free energies, total entropy was considered to explain the discrepancy between mCSM-AB2 predictions and experimental results. This study provides guidelines and identifies the limitations of mCSM-AB2 and MD simulations in antibody engineering.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432346","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}

引用次数: 0

How a mixture of microRNA-29a (miR-29a) and microRNA-144 (miR-144) cancer biomarkers interacts with a graphene quantum dot 癌症生物标记物 microRNA-29a (miR-29a) 和 microRNA-144 (miR-144) 的混合物如何与石墨烯量子点相互作用

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-12 DOI: 10.1016/j.jmgm.2024.108881

{"title":"How a mixture of microRNA-29a (miR-29a) and microRNA-144 (miR-144) cancer biomarkers interacts with a graphene quantum dot","authors":"","doi":"10.1016/j.jmgm.2024.108881","DOIUrl":"10.1016/j.jmgm.2024.108881","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) which are small non-coding RNAs have been reported to be potential cancer biomarker. However, it is difficult to extract such short RNA from a sample matrix. New effective strategies are required. Recently, graphene quantum dots (GQDs) have been used to detect nucleotides in many biosensor platforms, but their applications for miRNA extraction remain limited. GQD was reported to be able to collect short miRNA, but its performance to collect miRNAs with different structure remains unknown. Thus, in this work, the capability of GQD to interact with two different miRNAs is investigated. A mixture of hairpin-like miR-29a and circular miR-144 molecules are used as a representative of two miRNA morphologies. Two systems (a miRNA mixture, comprising 4 of miR-29a and 4 of miR-144, with (miR_GQD) and without GQD (miR)) were studied in comparison. MiRNAs in a mixture (miR) can aggregate, but no permanent miRNA assembly is captured. In contrast, the presence of GQD can rapidly and spontaneously activate the permanent miRNA/GQD clustering. This finding highlights the ability of GQD to be a miRNA collector. Interestingly, all GQD-bound miRNAs do not unfold. This allows the easy accessibility for probes. Also, nano-sized GQD seems to prefer hairpin miR-29a. The free 5’ terminus of miR-29a acts as the sticky end to adhere on GQD. This work highlights the importance of RNA secondary structure on GQD/miRNA aggregation capability. An insight obtained here will be useful for further design of miRNA isolation strategies.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440997","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}

引用次数: 0

Unwinding DNA strands by single-walled carbon nanotubes: Molecular docking and MD simulation approach 单壁碳纳米管解开 DNA 链：分子对接和 MD 模拟方法

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-11 DOI: 10.1016/j.jmgm.2024.108882

{"title":"Unwinding DNA strands by single-walled carbon nanotubes: Molecular docking and MD simulation approach","authors":"","doi":"10.1016/j.jmgm.2024.108882","DOIUrl":"10.1016/j.jmgm.2024.108882","url":null,"abstract":"<div><div>Despite the growing research into the use of carbon nano-tubes (CNTs) in science and medicine, concerns about their potential toxicity remain insufficiently studied. This study utilizes molecular docking calculations combined by molecular dynamics simulations to investigate the dynamic intricacies of the interaction between single-walled carbon nanotubes (swCNTs) and double-stranded DNA (dsDNA). By examining the influence of swCNT characteristics such as length, radius, and chirality, our findings shed light on the complex interplay that shapes the binding affinity and stability of the dsDNA-swCNT complex. Molecular docking results identify a zigzag swCNT, with a radius of 0.16 Å and a length of 38 Å, as exhibiting the highest binding affinity with dsDNA (−23.9 kcal/mol). Comprehensive analyses, spanning docking results, binding energies, RMSD, radius of gyration, and potential of mean force (PMF) profiles, provide a detailed understanding of the denaturation dynamics. The PMF profiles reveal the thermodynamic feasibility of the DNA-CNT interaction, outlining distinct energy landscapes and barriers: when the selected swCNT binds within the dsDNA groove, the system becomes trapped at the first and second local energy minima, occurring at 1.48 nm and 1.00 nm, respectively. Intramolecular hydrogen bond calculations show a significant reduction, affirming the denaturing effect of swCNTs on DNA. Furthermore, the study reveals a significant reduction in the binding affinity of Ethidium Bromide (EB) to dsDNA following its interaction with swCNT, with a decrease in EB binding to dsDNA of approximately 13.2 %. This research offers valuable insights into the toxic effects of swCNTs on dsDNA, contributing to a rationalization of the cancerous potential of swCNTs.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432344","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}

引用次数: 0

Insights into the binding recognition and computational design of IL-2 muteins with enhanced predicted binding affinity to the IL-2 receptor α 对与 IL-2 受体 α 结合亲和力预测增强的 IL-2 静音素的结合识别和计算设计的深入研究

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-11 DOI: 10.1016/j.jmgm.2024.108883

{"title":"Insights into the binding recognition and computational design of IL-2 muteins with enhanced predicted binding affinity to the IL-2 receptor α","authors":"","doi":"10.1016/j.jmgm.2024.108883","DOIUrl":"10.1016/j.jmgm.2024.108883","url":null,"abstract":"<div><div>Interleukin-2 (IL-2) is an immune system regulator that has received approval for cancer treatment. However, high-dose IL-2 therapy has seen restricted use due to its low efficacy and on-target toxicity. To enhance the effectiveness of IL-2 therapy, it is essential to engineer IL-2 molecules to enhance their specificity toward target cell populations. In this study, molecular dynamics (MD) simulations and Rosetta software were utilized to design novel high-affinity IL-2Rα-binding IL-2 muteins. MD simulations were used to identify the target residues of IL-2 for design, and Rosetta software were then employed to predict potential IL-2 muteins with higher binding affinity toward IL-2Rα. Rosetta generated two potential designed IL-2 muteins. The results of the MD validation and MM/GBSA analysis indicated that both designed IL-2 muteins exhibited greater predicted binding affinities toward IL-2Rα than that of the native proteins. RMSF analysis demonstrated that the structural fluctuations of free IL-2 and designed muteins were similar, indicating that the mutations did not alter the intramolecular force responsible for IL-2's stability and folding. These designed IL-2 muteins may have potential benefits for cancer immunotherapy.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142432345","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}

引用次数: 0

Adsorption dynamics of heavy oil droplets on silica: Effect of asphaltene anionic carboxylic 重油液滴在二氧化硅上的吸附动力学：沥青阴离子羧酸的影响

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-10 DOI: 10.1016/j.jmgm.2024.108880

引用次数: 0

Local potential energy density – A DFT analysis and the local binding energy in complexes with multiple interactions 局部势能密度 - DFT 分析和具有多重相互作用的复合物的局部结合能

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-09 DOI: 10.1016/j.jmgm.2024.108879

引用次数: 0

Dy-SheHeRASADe: A representation of the β sheet dynamics through surface descriptors Dy-SheHeRASADe：通过表面描述符表征 β 片层动力学。

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-05 DOI: 10.1016/j.jmgm.2024.108876

{"title":"Dy-SheHeRASADe: A representation of the β sheet dynamics through surface descriptors","authors":"","doi":"10.1016/j.jmgm.2024.108876","DOIUrl":"10.1016/j.jmgm.2024.108876","url":null,"abstract":"<div><div>Molecular dynamics (MD) simulations are important tools for studying the dynamic motions of macromolecules at the atomic level. With the increasing capabilities of high performance computing, MD simulations are becoming more widely used. This allows molecular modelers to simulate the molecular behavior of large molecular architectures for much longer trajectories. Appropriate visualization of MD trajectories is becoming essential to provide an immediate and intuitive understanding of a molecule’s dynamics and function. In this study, we implement a novel 3D graphical representation, Dynamical Sheets Helper for RepresentAtion of SurfAce Descriptors (Dy-SheHeRASADe), to visualize the <span><math><mi>β</mi></math></span> sheet secondary structures of proteins in the context of molecular dynamics. Dy-SheHeRASADe is developed in UnityMol, an open source molecular viewer and prototyping platform. We considered <span><math><mi>β</mi></math></span> sheet fluctuations and hydrogen bond formation during molecular dynamics simulations to characterize the parts of <span><math><mi>β</mi></math></span> sheets with large motions or with labile bonds. We propose two visualization modes based on a surface representation of the <span><math><mi>β</mi></math></span> sheets calculated according to the positions of the <span><math><mi>α</mi></math></span> carbons and the hydrogen bonds between the <span><math><mi>β</mi></math></span> strands. The volumetric mode, in which this surface is enclosed in a semi-transparent volume that represents the fluctuation zone of the sheet during dynamics. The heatmap mode, in which the surface is colored according to the amplitude values of the <span><math><mi>α</mi></math></span> carbons. In addition, we quantify the <span><math><mi>β</mi></math></span> sheet fluctuations by displaying the values of the largest and smallest movements of the <span><math><mi>β</mi></math></span> sheets, the surface area of the sheets, and the number of hydrogen bonds.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the optical properties of naphdiyne sheet: First-principles study 探索萘二炔薄片的光学特性：第一原理研究。

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-10-04 DOI: 10.1016/j.jmgm.2024.108877

引用次数: 0

Evaluation of AlphaFold3 for the fatty acids docking to human fatty acid-binding proteins 评估 AlphaFold3 与人类脂肪酸结合蛋白的脂肪酸对接。

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-09-27 DOI: 10.1016/j.jmgm.2024.108872

{"title":"Evaluation of AlphaFold3 for the fatty acids docking to human fatty acid-binding proteins","authors":"","doi":"10.1016/j.jmgm.2024.108872","DOIUrl":"10.1016/j.jmgm.2024.108872","url":null,"abstract":"<div><div>Human fatty acid-binding proteins (FABPs) are involved in many aspects of lipid metabolism, such as the uptake, transport, and storage of lipophilic molecules, as well as cellular functions. Understanding how FABPs recognize fatty acids (FAs) is crucial for identifying FABP function and applications, such as in inhibitor design or biomarker development. The recently developed AlphaFold3 (AF3) demonstrates significantly higher accuracy than other prediction tools, particularly in predicting protein–ligand interactions with state-of-the-art docking tools. Studies on whether AF3 can be used to identify the FAs of FABP are lacking. To assess the accuracy of FA docking to FABPs using AF3, models of FA docked into FABP generated using AF3 were compared with experimentally determined FA-bound FABP structures. FA ligands in AF3 structures docked reliably into the FA-binding pocket of FABPs; however, the detailed binding configuration of most FA ligands docked into FABPs and the interaction between FA and FABP determined using AF3 and experimentally differed. These results will aid in understanding FA docking to FABPs and other FA-binding proteins using AF3.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372074","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}

引用次数: 0

Modification of MM force fields around heme-Fe in the CYP–ligand complex and ab initio FMO calculations for the complex 修改 CYP 配体复合物中血红素-铁周围的 MM 力场，并对该复合物进行 ab initio FMO 计算。

IF 2.7 4区生物学

Journal of molecular graphics & modelling Pub Date : 2024-09-26 DOI: 10.1016/j.jmgm.2024.108875

{"title":"Modification of MM force fields around heme-Fe in the CYP–ligand complex and ab initio FMO calculations for the complex","authors":"","doi":"10.1016/j.jmgm.2024.108875","DOIUrl":"10.1016/j.jmgm.2024.108875","url":null,"abstract":"<div><div>Cytochrome P450 (CYP) enzymes play essential roles in the synthesis and metabolic activation of physiologically active substances. CYP has a prosthetic heme (iron protoporphyrin IX) in its active center, where Fe ion (heme-Fe) is deeply involved in enzymatic reactions of CYP. To precisely describe the structure and electronic states around heme-Fe, we modified the force fields (FFs) around heme-Fe in molecular mechanics (MM) simulations and conducted <em>ab initio</em> fragment molecular orbital (FMO) calculations for the CYP–ligand complex. To describe the coordination bond between heme-Fe and its coordinated ligand (ketoconazole), we added FF between heme-Fe and the N atom of ketoconazole, and then the structure of the complex was optimized using the modified FF. Its adequacy was confirmed by comparing the MM-optimized structure with the X-ray crystal one of the CYP–ketoconazole complex. We also performed 100 ns molecular dynamics simulations and revealed that the coordination bonds around heme-Fe were maintained even at 310 K and that the CYP–ketoconazole structure was kept similar to the X-ray structure. Furthermore, we investigated the electronic states of the complex using the <em>ab initio</em> FMO method to identify the CYP residues and parts of ketoconazole that contribute to strong binding between CYP and ketoconazole. The present procedure of constructing FF between heme-Fe and ketoconazole can be applicable to other CYP–ligand complexes, and the modified FF can provide their accurate structures useful for predicting the specific interactions between CYP and its ligands.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372075","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}

引用次数: 0