Journal of molecular graphics & modelling最新文献_第3页

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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-12 DOI: 10.1016/j.jmgm.2024.108881

Darunee Traiphothon , Tadsanee Awang , Nattapon Kuntip , Deanpen Japrung , Prapasiri Pongprayoon

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.

据报道，微小 RNA（miRNA）是一种小型非编码 RNA，是潜在的癌症生物标志物。然而，从样本基质中提取这种短 RNA 十分困难。因此需要新的有效策略。最近，石墨烯量子点（GQDs）已在许多生物传感器平台中用于检测核苷酸，但其在 miRNA 提取方面的应用仍然有限。据报道，GQD 能够收集短 miRNA，但其收集不同结构 miRNA 的性能仍然未知。因此，这项工作研究了 GQD 与两种不同 miRNA 相互作用的能力。发夹状 miR-29a 和环状 miR-144 分子的混合物被用作两种 miRNA 形态的代表。比较研究了两个系统（miRNA 混合物，包括 4 个 miR-29a 和 4 个 miR-144，含（miR_GQD）和不含 GQD（miR））。混合物（miR）中的 miRNA 可以聚集，但没有捕获到永久性的 miRNA 集合。相比之下，GQD 的存在能迅速、自发地激活永久性 miRNA/GQD 聚集。这一发现凸显了 GQD 成为 miRNA 收集器的能力。有趣的是，所有与 GQD 结合的 miRNA 都不会展开。这使得探针很容易进入。此外，纳米级 GQD 似乎更喜欢发夹型 miR-29a。miR-29a 的自由 5' 末端是粘附在 GQD 上的粘性末端。这项工作强调了 RNA 二级结构对 GQD/miRNA 聚集能力的重要性。这一发现将有助于进一步设计 miRNA 分离策略。

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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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-11 DOI: 10.1016/j.jmgm.2024.108882

Ghazal Borhan, Mehdi Sahihi

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.

尽管有关碳纳米管（CNTs）在科学和医学领域应用的研究日益增多，但人们对其潜在毒性的担忧仍未得到充分研究。本研究利用分子对接计算结合分子动力学模拟来研究单壁碳纳米管（swCNTs）与双链 DNA（dsDNA）之间错综复杂的动态相互作用。通过研究 swCNT 特征（如长度、半径和手性）的影响，我们的研究结果揭示了形成 dsDNA-swCNT 复合物结合亲和力和稳定性的复杂相互作用。分子对接结果表明，半径为 0.16 Å、长度为 38 Å 的人字形 swCNT 与 dsDNA 的结合亲和力最高（-23.9 kcal/mol）。从对接结果、结合能、RMSD、回旋半径和平均力势（PMF）曲线等方面进行综合分析，可以详细了解变性动力学。PMF 曲线揭示了 DNA-CNT 相互作用的热力学可行性，勾勒出不同的能量景观和障碍：当选定的 swCNT 与 dsDNA 沟槽结合时，系统会被困在第一和第二个局部能量最小值处，分别为 1.48 nm 和 1.00 nm。分子内氢键计算结果表明，该效应显著降低，从而证实了 swCNT 对 DNA 的变性作用。此外，研究还发现，溴化乙锭（EB）与 swCNT 相互作用后，与 dsDNA 的结合亲和力显著降低，EB 与 dsDNA 的结合降低了约 13.2%。这项研究为了解 swCNT 对 dsDNA 的毒性作用提供了宝贵的见解，有助于合理解释 swCNT 的致癌潜力。

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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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-11 DOI: 10.1016/j.jmgm.2024.108883

Thanapon Charoenwongpaiboon , Methus Klaewkla

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.

白细胞介素-2（IL-2）是一种免疫系统调节剂，已被批准用于癌症治疗。然而，由于低效和靶向毒性，大剂量 IL-2 疗法的使用受到了限制。为了提高IL-2疗法的疗效，必须对IL-2分子进行工程设计，以增强其对靶细胞群的特异性。本研究利用分子动力学（MD）模拟和Rosetta软件设计了新型高亲和力IL-2Rα结合型IL-2静音素。分子动力学模拟用于确定IL-2的目标残基，然后利用Rosetta软件预测与IL-2Rα结合亲和力更高的潜在IL-2静蛋白。Rosetta 生成了两种潜在的 IL-2 静蛋白。MD 验证和 MM/GBSA 分析的结果表明，这两种设计的 IL-2 muteins 对 IL-2Rα 的预测结合亲和力均高于原生蛋白。RMSF分析表明，游离IL-2和设计的静蛋白的结构波动相似，表明突变并没有改变导致IL-2稳定性和折叠的分子内力。这些设计的IL-2静音蛋白可能对癌症免疫疗法有潜在的益处。

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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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-10 DOI: 10.1016/j.jmgm.2024.108880

Peng Cui , Heng Zhang , Shiling Yuan

Understanding the adsorption behavior of asphaltene molecules on the surfaces of oil reservoir solids is essential for optimizing oil recovery processes. This study employed molecular dynamics simulations to investigate the adsorption behavior of oil droplets composed of charged and neutral asphaltenes on silica surfaces. The results revealed that oil droplet containing anionic asphaltene molecules were more likely to adsorb onto silica surfaces and exhibited greater resistance to detachment compared to oil droplet containing neutral asphaltene molecules. Specifically, anionic asphaltene molecules tended to accumulate at the oil-water-silica interface, whereas neutral asphaltene molecules primarily adsorbed near the oil-water interface. These findings provide valuable insights into the differing adsorption dynamics of charged and neutral asphaltene molecules on silica surfaces.

了解沥青质分子在油藏固体表面的吸附行为对于优化采油过程至关重要。本研究采用分子动力学模拟来研究由带电和中性沥青质组成的油滴在二氧化硅表面的吸附行为。结果表明，与含有中性沥青质分子的油滴相比，含有阴离子沥青质分子的油滴更容易吸附到二氧化硅表面，并表现出更强的抗脱离能力。具体来说，阴离子沥青质分子倾向于积聚在油-水-二氧化硅界面上，而中性沥青质分子则主要吸附在油-水界面附近。这些发现为了解带电沥青质分子和中性沥青质分子在二氧化硅表面的不同吸附动力学提供了宝贵的见解。

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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-09 DOI: 10.1016/j.jmgm.2024.108879

Caio L. Firme

A recently developed method, so-called local potential energy density, LPED, provides the binding energy density of intra/intermolecular interactions. The LPED cannot directly give the binding energy of intra/intermolecular interactions. However, it can indirectly give the binding energy through the linear equation between LPED and supramolecular binding energy, SME. In addition, the LPED can be used to obtain the SME of local or individual interactions indirectly for the case of complexes with multiple interactions, which cannot be obtained for any other method to our knowledge. The calculation of the LPED was evaluated with three different levels of theory using density functional methods. The linearity of LPED and SME between the reference level of theory (ωB97X-D/aug-cc-pVTZ) and the other levels of theory are similar among the studied levels of theory. In addition, LPED was used indirectly to obtain the local binding energy of intermolecular interactions of complexes with multiple interactions, such as the EDTA-Ca⁺² and the fosfomycin-Ca⁺².

最近开发的一种方法，即所谓的局部势能密度（LPED），可提供分子内/分子间相互作用的结合能密度。LPED 不能直接给出分子内/分子间相互作用的结合能。不过，它可以通过 LPED 与超分子结合能 SME 之间的线性方程间接给出结合能。此外，对于具有多重相互作用的复合物，LPED 还可用于间接获得局部或单个相互作用的 SME，而据我们所知，任何其他方法都无法获得 SME。我们使用密度泛函方法，在三种不同的理论水平上对 LPED 的计算进行了评估。在所研究的理论水平中，参考理论水平（ωB97X-D/aug-cc-pVTZ）和其他理论水平之间的 LPED 线性和 SME 相似。此外，LPED 被间接用于获得具有多重相互作用的复合物（如 EDTA-Ca+2 和磷霉素-Ca+2）分子间相互作用的局部结合能。

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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-05 DOI: 10.1016/j.jmgm.2024.108876

Hayet Belghit, Manuel Dauchez, Jean-Marc Crowet, Jessica Jonquet-Prevoteau

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

β

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

β

sheet fluctuations and hydrogen bond formation during molecular dynamics simulations to characterize the parts of

β

sheets with large motions or with labile bonds. We propose two visualization modes based on a surface representation of the

β

sheets calculated according to the positions of the

α

carbons and the hydrogen bonds between the

β

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

α

carbons. In addition, we quantify the

β

sheet fluctuations by displaying the values of the largest and smallest movements of the

β

sheets, the surface area of the sheets, and the number of hydrogen bonds.

分子动力学（MD）模拟是研究原子水平大分子动态运动的重要工具。随着高性能计算能力的不断提高，分子动力学模拟的应用也越来越广泛。这使得分子建模人员能够模拟大分子结构的分子行为，获得更长的轨迹。适当的 MD 轨迹可视化对于即时直观地了解分子动力学和功能至关重要。在这项研究中，我们采用了一种新颖的三维图形表示法--表面描述符表示法的动态薄片助手（Dy-SheHeRASADe），在分子动力学背景下可视化蛋白质的β薄片二级结构。Dy-SheHeRASADe 是在开源分子浏览器和原型平台 UnityMol 中开发的。我们考虑了分子动力学模拟过程中的β片层波动和氢键形成，以描述β片层中运动较大或有易变键的部分。我们提出了两种可视化模式，它们基于根据 α 碳的位置和 β 链之间的氢键计算出来的 β 片的表面表示。体积模式：该表面被封闭在一个半透明的体积中，该体积代表薄片在动力学过程中的波动区域。热图模式：根据 α 碳的振幅值对表面进行着色。此外，我们还通过显示 β 片的最大和最小运动值、片的表面积和氢键数量来量化 β 片的波动。

{"title":"Dy-SheHeRASADe: A representation of the β sheet dynamics through surface descriptors","authors":"Hayet Belghit, Manuel Dauchez, Jean-Marc Crowet, Jessica Jonquet-Prevoteau","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":"133 ","pages":"Article 108876"},"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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-04 DOI: 10.1016/j.jmgm.2024.108877

Roya Majidi

Naphdiyne sheet is a two-dimensional carbon-based structure composed of naphthyl rings and acetylenic linkages. The optical characteristics of naphdiyne sheets are investigated using density functional theory. The results showed that this sheet is suitable for energy storage systems due to its high dielectric constant. The dielectric constant of naphdiyne is higher than that of graphene. The refractive index, absorption, reflection, and transmission coefficients are calculated based on the dielectric function. A notable optical absorption is observed across a wide energy range for parallel polarization. The transparency of this material is evident in its reflection and transmission constants, particularly in high-energy regions. The findings suggest that the naphdiyne sheets hold promise for use in nanoelectronics and optoelectronics.

萘二炔薄片是一种由萘环和乙炔连接组成的二维碳基结构。研究人员利用密度泛函理论研究了萘二乙烯薄片的光学特性。结果表明，这种薄片因其介电常数高而适用于储能系统。萘二炔的介电常数高于石墨烯。根据介电函数计算了折射率、吸收、反射和透射系数。在平行极化的宽能量范围内观察到了显著的光吸收现象。这种材料的透明度在其反射和透射常数中体现得非常明显，尤其是在高能量区域。研究结果表明，萘二炔薄片有望用于纳米电子学和光电子学。

引用次数: 0

Bjerrum defects in s-II gas hydrate s-II 气体水合物中的 Bjerrum 缺陷。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-04 DOI: 10.1016/j.jmgm.2024.108878

Nevin Uras-Aytemiz , F. Mine Balcı

The energy and structure of Bjerrum defects in structure II gas hydrates were investigated by using first-principle calculations for finite-size clusters and periodic 3D lattice systems. The formation energies of these defects were calculated for the first time when the cages of the structure II structure were completely empty and the large cage was filled with a THF molecule. Analogous to findings in ice structures, one of the hydrogen atoms forming the D defect was noted to orient toward the cage. If the excess proton resides in the large cage, it acts as an attraction center for the polar guest molecule, i.e., THF. Therefore, the large cage guest THF molecule stabilizes the D/L defect pair and isolated D/L defect formation energies by forming hydrogen bonds with the D defect. In such cases, the defect structure representing a D/L defect pair containing a THF molecule interacting with one of the hydrogen atoms of the D defect mirrors the guest-induced ones. Notably, the classical Bjerrum defect and the guest-induced Bjerrum defect exhibit a similar phenomenon in defective structures. Contrary to existing literature, it is evident that guest-induced Bjerrum defects involve both the L and D components. The insights gained from this study could potentially offer an alternative perspective to understand various experimental observations, such as those related to dielectric and NMR properties.

通过对有限尺寸簇和周期性三维晶格系统进行第一性原理计算，研究了结构 II 气体水合物中 Bjerrum 缺陷的能量和结构。首次计算了当结构 II 的笼子完全为空且大笼子中充满一个 THF 分子时这些缺陷的形成能量。与冰结构中的发现类似，形成 D 缺陷的一个氢原子被注意到朝向笼。如果多余的质子位于大笼子中，它就会成为极性客体分子（即 THF）的吸引中心。因此，大笼客体 THF 分子通过与 D 缺陷形成氢键，稳定了 D/L 缺陷对并隔离了 D/L 缺陷形成能量。在这种情况下，代表含有与 D 缺陷的一个氢原子相互作用的 THF 分子的 D/L 缺陷对的缺陷结构反映了客体诱导的缺陷结构。值得注意的是，经典的 Bjerrum 缺陷和客体诱导的 Bjerrum 缺陷在缺陷结构中表现出类似的现象。与现有文献相反，客人诱导的 Bjerrum 缺陷显然涉及 L 和 D 两部分。从这项研究中获得的见解有可能为理解各种实验观察结果（如与介电和核磁共振特性相关的观察结果）提供另一种视角。

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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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-09-27 DOI: 10.1016/j.jmgm.2024.108872

Ki Hyun Nam

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.

人类脂肪酸结合蛋白（FABPs）参与脂质代谢的许多方面，如亲脂性分子的摄取、运输和储存以及细胞功能。了解 FABP 如何识别脂肪酸（FA）对于确定 FABP 的功能和应用（如抑制剂设计或生物标记物开发）至关重要。最近开发的 AlphaFold3（AF3）显示出明显高于其他预测工具的准确性，特别是在预测与最先进对接工具的蛋白质配体相互作用方面。目前还缺乏有关 AF3 是否可用于识别 FABP 的 FA 的研究。为了评估使用 AF3 将 FA 与 FABP 对接的准确性，将使用 AF3 生成的 FA 与 FABP 对接的模型与实验测定的 FA 结合 FABP 结构进行了比较。AF3结构中的FA配体可靠地对接了FABPs的FA结合口袋；然而，大多数对接FABPs的FA配体的详细结合构型以及使用AF3确定的FA与FABP之间的相互作用与实验结果不同。这些结果将有助于理解使用 AF3 将 FA 与 FABPs 及其他 FA 结合蛋白对接的过程。

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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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-09-26 DOI: 10.1016/j.jmgm.2024.108875

Yoshinobu Nagura, Haruna Sabishiro, Nagomi Chimura, Masayuki Yuguchi, Narutoshi Tada, Daichi Takimoto, Noriyuki Kurita

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 ab initio 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 ab initio 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.

细胞色素 P450（CYP）酶在生理活性物质的合成和代谢活化过程中发挥着重要作用。CYP 的活性中心有一个修复血红素（铁原卟啉 IX），其中的铁离子（血红素-铁）深度参与了 CYP 的酶促反应。为了精确描述血红素-铁周围的结构和电子状态，我们在分子力学（MM）模拟中修改了血红素-铁周围的力场（FFs），并对 CYP 配体复合物进行了 ab initio 片段分子轨道（FMO）计算。为了描述血红素-铁与其配位体（酮康唑）之间的配位键，我们在血红素-铁与酮康唑的 N 原子之间添加了 FF，然后使用修改后的 FF 对复合物结构进行了优化。通过将 MM 优化后的结构与 CYP-酮康唑复合物的 X 射线晶体结构进行比较，证实了 MM 结构的适当性。我们还进行了 100 ns 的分子动力学模拟，结果表明，即使在 310 K 的温度下，血红素-铁周围的配位键仍然保持不变，CYP-酮康唑的结构也与 X 射线结构相似。此外，我们还利用 ab initio FMO 方法研究了复合物的电子态，以确定 CYP 残基和酮康唑中有助于 CYP 与酮康唑强结合的部分。本研究构建血红素-铁和酮康唑之间的 FF 的过程可适用于其他 CYP 配体复合物，修饰后的 FF 可提供其精确结构，有助于预测 CYP 与其配体之间的特定相互作用。

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引用次数: 0