Journal of molecular graphics & modelling最新文献_第2页

Comparative study of various molecular feature representations for solvation free energy predictions of neutral species 用于预测中性物种溶解自由能的各种分子特征表示的比较研究。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-11-01 DOI: 10.1016/j.jmgm.2024.108901

Valerii V. Isaev , Yury Minenkov

Predicting molecular properties with the help of Neural Networks is a common way to substitute or enhance comprehensive quantum-chemical calculations. One of the problems facing researchers is the choice of vectorization approach to representing the solvent and the solute for the estimator model. In this work, 10 different approaches have been investigated for both organic solute and solvent including vectorizers that relied on macroscopic parameters, functional groups classification, molecular graphs, or atomic coordinates. A variation of the Bag of Bonds approach called JustBonds, trained on the MNSol database, showed the best overall performance resulting in RMSD <2 kcal/mol for the blind dataset that contains the solutes not presented in the training subset and <1 kcal/mol on records from Solv@TUM database, which is close to contemporary continuum models. We have also demonstrated that the most important bags usually contain heteroatom and play a key role in the solvation process. Furthermore, the small role of solvent vectorization was demonstrated and revealed that approaches based on functional groups or macroscopic solvent parameters are often enough to efficiently represent solvent media.

在神经网络的帮助下预测分子特性是替代或增强综合量子化学计算的常用方法。研究人员面临的问题之一是如何选择矢量化方法来表示估算模型中的溶剂和溶质。在这项工作中，针对有机溶质和溶剂研究了 10 种不同的方法，包括依赖宏观参数、官能团分类、分子图或原子坐标的矢量化方法。在 MNSol 数据库上训练的名为 "JustBonds "的 "Bag of Bonds "方法变体显示出最佳的整体性能，其 RMSD

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引用次数: 0

Effect of channel roughness on the particle diffusion and permeability of carbon nanotubes in reverse electrodialysis process applying molecular dynamics simulation 应用分子动力学模拟研究反向电渗析过程中通道粗糙度对碳纳米管颗粒扩散和渗透性的影响。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-30 DOI: 10.1016/j.jmgm.2024.108899

Yabing Li , Ali B.M. Ali , Nelly Esther Flores Tapia , Nargiza Kamolova , Soheil Salahshour , Rozbeh Sabetvand

Innovative technology and methods are crucial for making pure and refreshing water. Two main methods are present to delete soluble salts from water: membrane processes and thermal processes. A beneficial membrane technique is reverse electrodialysis. This research used molecular dynamics (MD) simulation to investigate how channel roughness affected particle diffusion and permeability in carbon nanotubes (CNTs) via the reverse electrodialysis process. The results indicate that adding roughness in the CNT duct increased the force between the primary fluid and the duct. Using an armchair-edged CNT structure maximized the electric current in the sample. Furthermore, the roughness increased the intensity of force in the channel, which was due to gravity, leading to a decrease in the mobility of fluid particles. Additionally, several broken hydrogen bonds inside the simulation box increased from 116 to 128 in the duct sample with roughness.

创新技术和方法对于制造纯净清爽的水至关重要。从水中去除可溶性盐分的方法主要有两种：膜法和热法。一种有效的膜技术是反向电渗析。本研究利用分子动力学（MD）模拟来研究通道粗糙度如何通过反向电渗析过程影响碳纳米管（CNTs）中颗粒的扩散和渗透性。结果表明，在 CNT 管道中增加粗糙度会增加原生流体与管道之间的作用力。使用 "扶手椅 "边缘的碳纳米管结构可使样品中的电流最大化。此外，由于重力作用，粗糙度增加了通道中的力强度，导致流体颗粒的流动性降低。此外，在带有粗糙度的管道样品中，模拟盒内断裂的氢键从 116 个增加到 128 个。

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引用次数: 0

Molecular dynamics simulations, essential dynamics and MMPBSA to evaluate natural compounds as potential inhibitors for AccD6, a key drug target in the fatty acid biosynthesis pathway in Mycobacterium tuberculosis 利用分子动力学模拟、基本动力学和 MMPBSA 评估天然化合物作为 AccD6（结核分枝杆菌脂肪酸生物合成途径中的一个关键药物靶点）潜在抑制剂的效果

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-28 DOI: 10.1016/j.jmgm.2024.108898

Chandra Jyoti Singha, Ramadas Krishna

Antibiotic resistance in Mycobacterium tuberculosis, the primary causative agent of the tuberculosis disease is an ever growing threat especially in developing and underdeveloped countries. Isoniazid is a commonly used first line anti-tuberculosis drug used during the first phase of tuberculosis treatment. However, due to its improper use, many strains of Mycobacterium tuberculosis have acquired resistance to the drug. Advancements in next generation sequencing technologies, such as transcriptomics have paved way for identifying alternative drug targets based on the differential expression pattern of genes. Therefore, this study makes use of RNA-Seq data of Mycobacterium tuberculosis isolates treated with different concentrations of isoniazid to identify genes that can be proposed as drug targets. From the differential expression analysis, it was observed that four genes were significantly upregulated under all the conditions. Among the four genes, accD6 was selected as the drug target for virtual screening and molecular dynamics studies, because of its role in fatty acid elongation and contribution to the synthesis of mycolic acids. The protein-protein interaction network and gene ontology based functional enrichment studies show an enrichment in fatty acid biosynthesis related pathways. Furthermore, virtual screening studies successfully screened the top three natural inhibitor molecules with satisfactory ADME properties and a better glide score than the reference compound, NCI-172033. The trajectory analysis, essential dynamics studies and MMPBSA analysis, concluded that among the hit molecules, NPC41982, a thiazole derivative showed the most promising results and can be considered as a potential drug candidate.

结核分枝杆菌是结核病的主要致病菌，其抗生素耐药性是一个日益严重的威胁，尤其是在发展中国家和欠发达国家。异烟肼是结核病治疗第一阶段常用的一线抗结核药物。然而，由于使用不当，许多结核分枝杆菌菌株对这种药物产生了抗药性。下一代测序技术（如转录组学）的进步为根据基因的差异表达模式确定替代药物靶点铺平了道路。因此，本研究利用用不同浓度异烟肼处理的结核分枝杆菌分离株的 RNA-Seq 数据来确定可作为药物靶点的基因。通过差异表达分析发现，有四个基因在所有条件下都显著上调。在这四个基因中，accD6因其在脂肪酸伸长过程中的作用和对霉酚酸合成的贡献而被选为虚拟筛选和分子动力学研究的药物靶标。基于蛋白质-蛋白质相互作用网络和基因本体论的功能富集研究表明，脂肪酸生物合成相关通路中存在富集。此外，虚拟筛选研究成功地筛选出了前三名天然抑制剂分子，它们具有令人满意的 ADME 特性，且滑翔得分优于参考化合物 NCI-172033。通过轨迹分析、基本动力学研究和 MMPBSA 分析，得出结论认为，在命中的分子中，噻唑衍生物 NPC41982 的结果最有希望，可作为潜在的候选药物。

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引用次数: 0

Molecular engineering on tyrian puprle natural dye as TiO2 based fined tuned photovoltaic dye material: DFT molecular analysis 作为基于二氧化钛的微调光伏染料材料的酪朊蛹天然染料的分子工程学：DFT 分子分析

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-26 DOI: 10.1016/j.jmgm.2024.108894

Cihat Güleryüz , Duha M. Hasan , Masar A. Awad , Azal S. Waheeb , Abrar U. Hassan , Ayesha Mohyuddin , Hussein A.K. Kyhoiesh , Mohammed T. Alotaibi

In this research, molecular modification is employed to see the enhancement in the efficiency of Tyrian Purple (TP), a natural dye, for organic photovoltaic materials. By using Density Functional Theory (DFT) based molecular modeling, seven new structures are designed with pi spacer to extend electron donor moieties. Teheir Frontier Molecular Orbital (FMO) analysis demonstartes their charges with a similar pattern of distributions over their Highest Occupied and Lowed Unocuupied Molecular Orbitals (HOMO/lUMO). This analysls also show their energy gaps (E_gaps) to range around 2.97–3.02 eV. Their maximum absorption wavelength (λ_max) demosntartes 486–490 nm range to indicate their tendency of absorbing light efficiently. Their Transition Density Matrix (TDM) analysis also reveals their facile electronic transitions without a significant charges over spacers. From calculating their photovoltaic paramters, their Light Harvesting Efficiency (LHE) reaches to 72.4–95.5 %. Also their Open Circuit Voltage (V_oc) varies across 1.16–1.34 V. It is found that dyes actively adsorb onto TiO₂ clusters to demonstrate their promise for tuning their Conduction Band (CB). This research is an effort for to evaluate the structural correlations to the develop photovoltaic materials through molecular-level design and optimization.

本研究采用分子修饰技术来提高天然染料泰利安紫（TP）用于有机光伏材料的效率。通过使用基于密度泛函理论（DFT）的分子建模，设计出了七种带有π间隔物的新结构，以扩展电子供体分子。它们的前沿分子轨道（FMO）分析表明，它们的电荷在最高占位和最低未占位分子轨道（HOMO/lUMO）上的分布模式相似。该分析还显示它们的能隙（Egaps）在 2.97-3.02 eV 左右。它们的最大吸收波长（λmax）介于 486-490 纳米之间，表明它们具有高效吸收光的倾向。它们的跃迁密度矩阵（TDM）分析也表明，它们的电子跃迁非常容易，不会在间隔物上产生大量电荷。通过计算它们的光伏参数，它们的光收集效率（LHE）达到 72.4-95.5%。此外，它们的开路电压（Voc）在 1.16-1.34 V 之间变化。研究发现，染料会主动吸附到二氧化钛团簇上，这证明它们有望调整其传导带（CB）。这项研究旨在通过分子层面的设计和优化，评估开发光伏材料的结构相关性。

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引用次数: 0

Unraveling the adsorption dynamics of asphaltene molecules on silica surfaces 揭示沥青分子在二氧化硅表面的吸附动力学。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-26 DOI: 10.1016/j.jmgm.2024.108897

Fengfeng Gao

Understanding the adsorption behavior of heavy oil components on reservoir solids is crucial for improving oil recovery, yet the molecular mechanism remains unclear. This study used molecular dynamics simulations to explore the adsorption kinetics and thermodynamics of asphaltene molecules on silica surfaces. The adsorption process was divided into three stages: free, adsorption, and equilibrium. In the adsorption stage, asphaltenes must pass through two dense hydration layers and adhere to the silica surface in a flat configuration. Carboxyl groups increase asphaltene hydrophilicity, raising interaction energy with water molecules and hindering adsorption. In addition, two distinct hydration layers of water molecules on the silica surface. The first hydration layer, with a peak density of 2000 kg m⁻³, was located around 0.6 nm from the surface, driven by hydrogen bonding between Si-OH groups and water molecules. The second layer, found at 1.44–1.80 nm, had a lower density of 1200 kg m⁻³, formed through hydrogen bonding between water molecules. This study aims to enhance the understanding of the physicochemical mechanisms governing oil droplet adsorption on silica surfaces, potentially informing the design of improved oil recovery strategies.

了解重油成分在储层固体上的吸附行为对提高石油采收率至关重要，但其分子机理仍不清楚。本研究利用分子动力学模拟来探索沥青质分子在二氧化硅表面的吸附动力学和热力学。吸附过程分为三个阶段：自由阶段、吸附阶段和平衡阶段。在吸附阶段，沥青质必须穿过两个致密的水合层，以平面构型附着在二氧化硅表面。羧基增加了沥青质的亲水性，提高了与水分子的相互作用能，阻碍了吸附。此外，二氧化硅表面有两个不同的水分子水合层。第一层水合层的峰值密度为 2000 kg m-3，位于距离表面 0.6 nm 左右的位置，由 Si-OH 基团和水分子之间的氢键驱动。第二层位于 1.44-1.80 纳米处，密度较低，为 1200 kg m-3，由水分子之间的氢键形成。这项研究旨在加深人们对硅表面吸附油滴的物理化学机制的了解，从而为改进采油战略的设计提供潜在的信息。

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引用次数: 0

QSPR modeling to predict surface tension of psychoanaleptic drugs using the hybrid DA-SVR algorithm 利用 DA-SVR 混合算法建立 QSPR 模型，预测精神药物的表面张力。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-23 DOI: 10.1016/j.jmgm.2024.108896

Meriem Ouaissa , Maamar Laidi , Othmane Benkortbi , Hasmerya Maarof

A robust Quantitative Structure-Property Relationship (QSPR) model was presented to predict the surface tension property of psychoanaleptic (psychostimulant and antidepressant) drugs. A dataset of 112 molecules was utilized, and three feature selection methods were applied: genetic algorithm combined with Ordinary Least Squares (GA-OLS), Partial Least Squares (GA-PLS), and Support Vector Machines (GA-SVM), each identifying ten pertinent AlvaDesc descriptors. The models were constructed using the Dragonfly Algorithm combined with the Support Vector Regressor (DA-SVR), with the GA-SVM-based model emerging as the top performer. Rigorous statistical metrics validate its superior predictive accuracy (R² = 0.98142, Q²_LOO = 0.98142, RMSE = 1.12836, AARD = 0.78746). Furthermore, an external test set of ten compounds was employed for model validation and extrapolation, along with assessing the applicability domain, further underscoring the model’s reliability. The selected descriptors (X0Av, VE1sign_B(e), ATSC1e, MATS6v, P_VSA_ppp_A, TDB01u, E1s, R2m+, N-067, SssO) collectively elucidate the key structural factors influencing surface tension in the studied drugs. The model provides excellent predictions and can be used to determine the surface tension of new psychoanaleptic drugs. Its outcomes will guide the design of novel medications with targeted surface tension properties.

本文提出了一种稳健的定量结构-性质关系（QSPR）模型，用于预测精神药物（精神刺激剂和抗抑郁药）的表面张力性质。研究利用了一个包含 112 种分子的数据集，并采用了三种特征选择方法：遗传算法结合普通最小二乘法（GA-OLS）、部分最小二乘法（GA-PLS）和支持向量机（GA-SVM），每种方法都能识别 10 个相关的 AlvaDesc 描述子。这些模型是使用蜻蜓算法结合支持向量调节器（DA-SVR）构建的，其中基于 GA-SVM 的模型表现最佳。严格的统计指标验证了其卓越的预测准确性（R2 = 0.98142，Q2LOO = 0.98142，RMSE = 1.12836，AARD = 0.78746）。此外，还采用了由 10 个化合物组成的外部测试集来验证和推断模型，同时评估了适用性领域，进一步强调了模型的可靠性。所选描述符（X0Av、VE1sign_B(e)、ATSC1e、MATS6v、P_VSA_ppp_A、TDB01u、E1s、R2m+、N-067、SssO）共同阐明了影响所研究药物表面张力的关键结构因素。该模型提供了很好的预测，可用于确定新型精神药物的表面张力。其结果将为设计具有针对性表面张力特性的新型药物提供指导。

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引用次数: 0

Evaluating interaction energy versus electron density relationships to estimate inter and intramolecular H-bonding 评估相互作用能与电子密度的关系，以估算分子间和分子内的氢键。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-22 DOI: 10.1016/j.jmgm.2024.108895

Murillo H. Queiroz , Suelen A. Santos , Joel L. Nascimento , Bruno S. Sampaio , Tiago V. Alves , Roberto Rivelino

We investigate the computational effects on the relationships between interaction energy (ΔE) and electron density (ρ), at the critical point obtained from 19 intermolecular H-bonded dimers, to estimate inter and intramolecular interactions of larger H-bonded systems. Our analysis examines basis set superposition error (BSSE) effects, dispersion energy corrections, and the exchange-correlation energy model on the ΔE vs. ρ linear regressions. The calculations were carried out within density functional theory (DFT) combined with the 6-31+G(d,p) and def2-TZVPP basis sets. This procedure quantifies the average effects of BSSE for different levels of approximation, and underscore the sensitivity of the ΔE estimation together with dispersion corrections. This is valuable for the development of DFT-based estimators of multiple interaction energies of large H-bonded systems with low computational cost. We have applied this procedure by analyzing H-bonded biological molecules, such as DNA base pairs, an asparagine side chain, and an AZT molecule. Our estimated H-bond interaction energies are in agreement with previous studies, and emphasize the importance of methodological considerations for accurately predicting interaction energies using DFT combined with topological parameters.

我们研究了从 19 个分子间 H 键二聚体得到的临界点上的相互作用能（ΔE）和电子密度（ρ）之间关系的计算影响，以估计较大 H 键体系的分子间和分子内相互作用。我们的分析考察了基集叠加误差 (BSSE) 效应、色散能修正以及交换相关能模型对 ΔE 与 ρ 线性回归的影响。计算是在密度泛函理论（DFT）中结合 6-31+G(d,p) 和 def2-TZVPP 基集进行的。这一过程量化了不同近似水平的 BSSE 平均效应，并强调了 ΔE 估计与弥散修正的敏感性。这对于以较低的计算成本开发基于 DFT 的大型 H 键体系多重相互作用能量估算器非常有价值。我们通过分析 DNA 碱基对、天冬酰胺侧链和 AZT 分子等 H 键生物分子应用了这一程序。我们估算的 H 键相互作用能与之前的研究结果一致，并强调了使用 DFT 结合拓扑参数准确预测相互作用能的方法论因素的重要性。

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引用次数: 0

Molecular dynamics simulations of hydrogen-bonded network structures of polybenzoxazines in the gas phase and aqueous solution 气相和水溶液中聚苯并恶嗪氢键网络结构的分子动力学模拟。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-18 DOI: 10.1016/j.jmgm.2024.108893

Pakuna Panbo , Uthen Thubsuang , Apirak Payaka

The crucial role of the amine functional group at the Mannich bridge of polybenzoxazines (PBZs) has been reported to be responsible for their hydrogen-bonded network structures. However, they have not been thoroughly studied in an aqueous solution and at the atomistic level. In this study, molecular dynamics simulations were applied to investigate the formation of hydrogen bond interactions of PBZs prepared from bisphenol A/methylamine (m-PBZ), bisphenol A/aniline-based (a-PBZ), and bisphenol A/2-(methylamino)ethylamine (e-PBZ). Based on the simulation results, the hydrogen-bonded network structures of the PBZs interfered with water molecules, leading to less compaction of the PBZ structure in the aqueous solution. The hydrogen bonding species of the m-PBZ and a-PBZ structures consisted of the –OH^…N (Mannich) and –OH^…O intramolecular interactions. However, for e-PBZ, the –OH^…O species was not present, but the 2-(ethylamino)ethylamine substituent formed more hydrogen bonding species than those of m-PBZ and a-PBZ. Additionally, the intermolecular hydrogen bond interactions of the PBZs and water molecules were not detected in any of the aqueous solution simulations.

据报道，聚苯并恶嗪（PBZs）曼尼希桥上的胺官能团对其氢键网络结构起着至关重要的作用。然而，人们尚未在水溶液和原子水平上对它们进行深入研究。本研究应用分子动力学模拟研究了由双酚 A/甲胺（m-PBZ）、双酚 A/苯胺基（a-PBZ）和双酚 A/2-（甲氨基）乙胺（e-PBZ）制备的 PBZ 的氢键相互作用的形成。根据模拟结果，PBZ 的氢键网络结构会干扰水分子，导致 PBZ 结构在水溶液中的压实度降低。m-PBZ和a-PBZ结构的氢键种类包括-OH...N（曼尼希）和-OH...O分子内相互作用。然而，对于 e-PBZ 来说，虽然不存在-OH...O 物种，但 2-（乙氨基）乙胺取代基形成的氢键种类却多于 m-PBZ 和 a-PBZ 的氢键种类。此外，在任何水溶液模拟中都没有检测到 PBZ 与水分子之间的分子间氢键相互作用。

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引用次数: 0

Designing of new functionalized imidazolium based ionic liquids attached to the antracene derivatives and investigation on the influence of intramolecular hydrogen bondings in anions on their intermolecular hydrogen bondings and some of the other properties: A DFT M06-2X-GD3 study 设计附着于蒽衍生物的新型官能化咪唑离子液体，并研究阴离子中分子内氢键对其分子间氢键及其他一些性质的影响：DFT M06-2X-GD3 研究。

IF 2.7 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-18 DOI: 10.1016/j.jmgm.2024.108885

Farzad Alijani Chakoli, Khatereh Ghauri, Farhad Shirini

To promote the development of new functionalized ionic liquids, it is necessary to get a deeper insight into their features of physicochemical and electronic and molecular structure. In this study, the interaction energies and structural and vibrational frequencies parameters in accompanied with some of the physiochemical, electronic and optic attributes of ionic liquids designed by the covalently attachement of imidazolium to anthracene derivatives ([X-AnMIM][A2] and [X-AnMIM][A3], X: NH₂, OH, OMe, H, Cl, CHO, CN and NO₂) ILs have been evaluated. Two conjugate bases of acids 1,3,5-pentanetriol (A2) and 3-(2-hydroxyethyl)-1,3,5-pentanetriol (A3) are used as anions which have two and three intramolecular hydrogen bonds, respectively. Based on the results of calculations at M06-2X-GD3/6–311++(d,p) level of theory, the differences in these properties in addition to the structural type of anions and cations can be attributed to the cation-anion, intra and intermolecular hydrogen bonding, interactions in ionic liquids. The results depict that the ILs based on A2 anions form stronger hydrogen bonds with [X-AnMIM]⁺ cations. The potency of interaction between cations and anion reduces with the increasement in the number of intramolecular hydrogen bonds and also decreasement in the basic strength in the anionic part. A clear red shift is observed between [X-AnMIM][A2] and [X-AnMIM][A3] ILs and isolated anthracene, which is a clear manifestation of the effect of the imidazolium cation on the electronic energy levels of anthracene. It can be expected that the studied ILs are not electrochemically stable during the electrochemistry applications.

为了促进新型功能化离子液体的开发，有必要深入了解其物理化学特征以及电子和分子结构。本研究评估了咪唑与蒽衍生物（[X-AnMIM][A2] 和 [X-AnMIM][A3]，X：NH2、OH、OMe、H、Cl、CHO、CN 和 NO2）共价连接设计的离子液体的相互作用能、结构和振动频率参数，以及一些物理化学、电子和光学属性。以 1,3,5-戊三醇（A2）和 3-（2-羟乙基）-1,3,5-戊三醇（A3）这两种酸的共轭碱作为阴离子，它们分别有两个和三个分子内氢键。根据 M06-2X-GD3/6-311++(d,p) 理论水平的计算结果，除了阴离子和阳离子的结构类型外，这些性质的差异还可归因于离子液体中阳离子-阴离子、分子内和分子间氢键的相互作用。结果表明，基于 A2 阴离子的离子液体能与 [X-AnMIM]+ 阳离子形成更强的氢键。阳离子和阴离子之间相互作用的效力随着分子内氢键数量的增加而降低，阴离子部分的碱性强度也随之降低。在[X-AnMIM][A2]和[X-AnMIM][A3] IL 与分离的蒽之间观察到明显的红移，这清楚地表明了咪唑阳离子对蒽电子能级的影响。可以预见，所研究的 IL 在电化学应用中并不具有电化学稳定性。

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引用次数: 0

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 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2024-10-13 DOI: 10.1016/j.jmgm.2024.108884

Thanathat Pamonsupornwichit , Kanchanok Kodchakorn , Piyachat Udomwong , Kanokporn Sornsuwan , Anuwat Weechan , On-anong Juntit , Piyarat Nimmanpipug , Chatchai Tayapiwatana

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 E. coli for subsequent binding property validation. Compared to WT HuScFvM6-1B9, the mutant HuScFvM6-1B9^L1:N32Y exhibited a 1.66-fold increase in binding affinity, with a K_D of 1.75 × 10⁻⁸ 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.

本研究旨在评估基于图谱的特征机器学习方法 mCSM-AB2 在人源化单链 Fv 抗 CD147（HuScFvM6-1B9）亲和力工程中的有效性。与此同时，还利用分子动力学（MD）模拟来深入了解 HuScFvM6-1B9-CD147 复合物的动力学和亲和力。结果分析包括将 mCSM-AB2 计算出的自由能变化与 MD 模拟预测的结合自由能进行整合。通过 MD 模拟得出的修饰后 HuScFvM6-1B9-CD147 结构域 1 复合物的模拟结构被用来突出参与结合面的关键残基。有趣的是，在与 31EDLGS35 表位相互作用的互补性决定区域，观察到 HuScFvM6-1B9 氨基酸模式的改变，尤其是在失去结合活性的突变体中。预测的 HuScFvM6-1B9 突变体随后被设计并在大肠杆菌中表达，以进行后续的结合特性验证。与 WT HuScFvM6-1B9 相比，突变体 HuScFvM6-1B9L1:N32Y 的结合亲和力提高了 1.66 倍，KD 为 1.75 × 10-8 M。除了结合自由能之外，还考虑了总熵来解释 mCSM-AB2 预测与实验结果之间的差异。本研究为 mCSM-AB2 和 MD 模拟在抗体工程中的应用提供了指导，并指出了其局限性。

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