Journal of Chemical Information and Modeling 最新文献

筛选
英文 中文
Accurately Modeling RNA Stem-Loops in an Implicit Solvent Environment 在隐含溶剂环境中精确建模 RNA 干环
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-13 DOI: 10.1021/acs.jcim.4c00756
Jason T. Linzer, Ethan Aminov, Aalim S. Abdullah, Colleen E. Kirkup, Rebeca I. Diaz Ventura, Vinay R. Bijoor, Jiyun Jung, Sophie Huang, Chi Gee Tse, Emily Álvarez Toucet, Hugo P. Onghai, Arghya P. Ghosh, Alex C. Grodzki, Emilee R. Haines, Aditya S. Iyer, Mark K. Khalil, Alexander P. Leong, Michael A. Neuhaus, Joseph Park, Asir Shahid, Matthew Xie, Jan M. Ziembicki, Carlos Simmerling, Maria C. Nagan
{"title":"Accurately Modeling RNA Stem-Loops in an Implicit Solvent Environment","authors":"Jason T. Linzer, Ethan Aminov, Aalim S. Abdullah, Colleen E. Kirkup, Rebeca I. Diaz Ventura, Vinay R. Bijoor, Jiyun Jung, Sophie Huang, Chi Gee Tse, Emily Álvarez Toucet, Hugo P. Onghai, Arghya P. Ghosh, Alex C. Grodzki, Emilee R. Haines, Aditya S. Iyer, Mark K. Khalil, Alexander P. Leong, Michael A. Neuhaus, Joseph Park, Asir Shahid, Matthew Xie, Jan M. Ziembicki, Carlos Simmerling, Maria C. Nagan","doi":"10.1021/acs.jcim.4c00756","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00756","url":null,"abstract":"Ribonucleic acid (RNA) molecules can adopt a variety of secondary and tertiary structures in solution, with stem-loops being one of the more common motifs. Here, we present a systematic analysis of 15 RNA stem-loop sequences simulated with molecular dynamics simulations in an implicit solvent environment. Analysis of RNA cluster ensembles showed that the stem-loop structures can generally adopt the A-form RNA in the stem region. Loop structures are more sensitive, and experimental structures could only be reproduced with modification of CH···O interactions in the force field, combined with an implicit solvent nonpolar correction to better model base stacking interactions. Accurately modeling RNA with current atomistic physics-based models remains challenging, but the RNA systems studied herein may provide a useful benchmark set for testing other RNA modeling methods in the future.","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Finding Relevant Retrosynthetic Disconnections for Stereocontrolled Reactions. 为立体可控反应寻找相关的逆合成断裂。
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-12 DOI: 10.1021/acs.jcim.4c00370
Olaf Wiest, Christoph Bauer, Paul Helquist, Per-Ola Norrby, Samuel Genheden
{"title":"Finding Relevant Retrosynthetic Disconnections for Stereocontrolled Reactions.","authors":"Olaf Wiest, Christoph Bauer, Paul Helquist, Per-Ola Norrby, Samuel Genheden","doi":"10.1021/acs.jcim.4c00370","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00370","url":null,"abstract":"<p><p>Machine learning-driven computer-aided synthesis planning (CASP) tools have become important tools for idea generation in the design of complex molecule synthesis but do not adequately address the stereochemical features of the target compounds. A novel approach to automated extraction of templates used in CASP that includes stereochemical information included in the US Patent and Trademark Office (USPTO) and an internal AstraZeneca database containing reactions from Reaxys, Pistachio, and AstraZeneca electronic lab notebooks is implemented in the freely available AiZynthFinder software. Three hundred sixty-seven templates covering reagent- and substrate-controlled as well as stereospecific reactions were extracted from the USPTO, while 20,724 templates were from the AstraZeneca database. The performance of these templates in multistep CASP is evaluated for 936 targets from the ChEMBL database and an in-house selection of 791 AZ designs. The potential and limitations are discussed for four case studies from ChEMBL and examples of FDA-approved drugs.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays. 基于配体的虚拟筛选,以发现对结核分枝杆菌有活性的强效 DNA 回旋酶 ATP 酶抑制剂吲哚衍生物,并通过生物检测验证命中率。
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-12 DOI: 10.1021/acs.jcim.4c00511
Bongkochawan Pakamwong, Paptawan Thongdee, Bundit Kamsri, Naruedon Phusi, Somjintana Taveepanich, Kampanart Chayajarus, Pharit Kamsri, Auradee Punkvang, Supa Hannongbua, Jidapa Sangswan, Khomson Suttisintong, Sanya Sureram, Prasat Kittakoop, Poonpilas Hongmanee, Pitak Santanirand, Jiraporn Leanpolchareanchai, James Spencer, Adrian J Mulholland, Pornpan Pungpo
{"title":"Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against <i>Mycobacterium tuberculosis</i> and Hit Validation by Biological Assays.","authors":"Bongkochawan Pakamwong, Paptawan Thongdee, Bundit Kamsri, Naruedon Phusi, Somjintana Taveepanich, Kampanart Chayajarus, Pharit Kamsri, Auradee Punkvang, Supa Hannongbua, Jidapa Sangswan, Khomson Suttisintong, Sanya Sureram, Prasat Kittakoop, Poonpilas Hongmanee, Pitak Santanirand, Jiraporn Leanpolchareanchai, James Spencer, Adrian J Mulholland, Pornpan Pungpo","doi":"10.1021/acs.jcim.4c00511","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00511","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. <i>M. tuberculosis</i> DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit <i>M. tuberculosis</i> GyrB ATPase activity from the Specs compound library. This approach yielded six compounds: four carbazole derivatives (<b>1</b>, <b>2</b>, <b>3</b>, and <b>8</b>), the benzoindole derivative <b>11</b>, and the indole derivative <b>14</b>. Carbazole derivatives can be considered a new scaffold for <i>M. tuberculosis</i> DNA gyrase ATPase inhibitors. IC<sub>50</sub> values of compounds <b>8</b>, <b>11</b>, and <b>14</b> (0.26, 0.56, and 0.08 μM, respectively) for inhibition of <i>M. tuberculosis</i> DNA gyrase ATPase activity are 5-fold, 2-fold, and 16-fold better than the known DNA gyrase ATPase inhibitor novobiocin. MIC values of these compounds against growth of <i>M. tuberculosis</i> H37Ra are 25.0, 3.1, and 6.2 μg/mL, respectively, superior to novobiocin (MIC > 100.0 μg/mL). Molecular dynamics simulations of models of docked GyrB:inhibitor complexes suggest that hydrogen bond interactions with GyrB Asp79 are crucial for high-affinity binding of compounds <b>8</b>, <b>11</b>, and <b>14</b> to <i>M. tuberculosis</i> GyrB for inhibition of ATPase activity. These data demonstrate that virtual screening can identify known and new scaffolds that inhibit both <i>M. tuberculosis</i> DNA gyrase ATPase activity in vitro and growth of <i>M. tuberculosis</i> bacteria.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular Mechanisms Underlying Single Nucleotide Polymorphism-Induced Reactivity Decrease in CYP2D6. 单核苷酸多态性诱导 CYP2D6 反应性降低的分子机制
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-12 DOI: 10.1021/acs.jcim.4c00276
Daniel Becker, Prasad V Bharatam, Holger Gohlke
{"title":"Molecular Mechanisms Underlying Single Nucleotide Polymorphism-Induced Reactivity Decrease in CYP2D6.","authors":"Daniel Becker, Prasad V Bharatam, Holger Gohlke","doi":"10.1021/acs.jcim.4c00276","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00276","url":null,"abstract":"<p><p>Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes involved in drug metabolism. Genetic polymorphism can influence drug metabolism by CYP2D6 such that a therapy is seriously affected by under- or overdosing of drugs. However, a general explanation at the atomistic level for poor activity is missing so far. Here we show for the 20 most common single nucleotide polymorphisms (SNPs) of CYP2D6 that poor metabolism is driven by four mechanisms. We found in extensive all-atom molecular dynamics simulations that the rigidity of the I-helix (central helix), distance between central phenylalanines (stabilizing bound substrate), availability of basic residues on the surface of CYP2D6 (binding of cytochrome P450 reductase), and position of arginine 132 (electron transfer to heme) are essential for an extensive function of the enzyme. These results were applied to SNPs with unknown effects, and potential SNPs that may lead to poor drug metabolism were identified. The revealed molecular mechanisms might be important for other drug-metabolizing cytochrome P450 enzymes.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
GOLEM: Automated and Robust Cryo-EM-Guided Ligand Docking with Explicit Water Molecules GOLEM:自动、稳健的低温电子显微镜引导配体与显性水分子对接
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-11 DOI: 10.1021/acs.jcim.4c00917
Zhiyu Zhao, Emad Tajkhorshid
{"title":"GOLEM: Automated and Robust Cryo-EM-Guided Ligand Docking with Explicit Water Molecules","authors":"Zhiyu Zhao, Emad Tajkhorshid","doi":"10.1021/acs.jcim.4c00917","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00917","url":null,"abstract":"A detailed understanding of ligand–protein interaction is essential for developing rational drug-design strategies. In recent years, technological advances in cryo-electron microscopy (cryo-EM) brought a new era to the structural determination of biological macromolecules and assemblies at high resolution, marking cryo-EM as a promising tool for studying ligand–protein interactions. However, even in high-resolution cryo-EM results, the densities for the bound small-molecule ligands are often of lower quality due to their relatively dynamic and flexible nature, frustrating their accurate coordinate assignment. To address the challenge of ligand modeling in cryo-EM maps, here we report the development of GOLEM (Genetic Optimization of Ligands in Experimental Maps), an automated and robust ligand docking method that predicts a ligand’s pose and conformation in cryo-EM maps. GOLEM employs a Lamarckian genetic algorithm to perform a hybrid global/local search for exploring the ligand’s conformational, orientational, and positional space. As an important feature, GOLEM explicitly considers water molecules and places them at optimal positions and orientations. GOLEM takes into account both molecular energetics and the correlation with the cryo-EM maps in its scoring function to optimally place the ligand. We have validated GOLEM against multiple cryo-EM structures with a wide range of map resolutions and ligand types, returning ligand poses in excellent agreement with the densities. As a VMD plugin, GOLEM is free of charge and accessible to the community. With these features, GOLEM will provide a valuable tool for ligand modeling in cryo-EM efforts toward drug discovery.","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
NRIMD, a Web Server for Analyzing Protein Allosteric Interactions Based on Molecular Dynamics Simulation 基于分子动力学模拟分析蛋白质异构相互作用的网络服务器 NRIMD
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-11 DOI: 10.1021/acs.jcim.4c00783
Yi He, Shuang Wang, Shuai Zeng, Jingxuan Zhu, Dong Xu, Weiwei Han, Juexin Wang
{"title":"NRIMD, a Web Server for Analyzing Protein Allosteric Interactions Based on Molecular Dynamics Simulation","authors":"Yi He, Shuang Wang, Shuai Zeng, Jingxuan Zhu, Dong Xu, Weiwei Han, Juexin Wang","doi":"10.1021/acs.jcim.4c00783","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00783","url":null,"abstract":"Long-range allosteric communication between distant sites and active sites in proteins is central to biological regulation but still poorly characterized, limiting the development of protein engineering and drug design. Addressing this gap, NRIMD is an open-access web server for analyzing long-range interactions in proteins from molecular dynamics (MD) simulations, such as the effect of mutations at distal sites or allosteric ligand binding at allosteric sites on the active center. Based on our recent works on neural relational inference using graph neural networks, this cloud-based web server accepts MD simulation data on any length of residues in the alpha-carbon skeleton format from mainstream MD software. The input trajectory data are validated at the frontend deployed on the cloud and then processed on the backend deployed on a high-performance computer system with a collection of complementary tools. The web server provides a one-stop-shop MD analysis platform to predict long-range interactions and their paths between distant sites and active sites. It provides a user-friendly interface for detailed analysis and visualization. To the best of our knowledge, NRIMD is the first-of-its-kind online service to provide comprehensive long-range interaction analysis on MD simulations, which significantly lowers the barrier of predictions on protein long-range interactions using deep learning. The NRIMD web server is publicly available at https://nrimd.luddy.indianapolis.iu.edu/.","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Riboflavin-Induced DNA Damage and Anticancer Activity in Breast Cancer Cells under Visible Light: A TD-DFT and In Vitro Study. 可见光下核黄素诱导的乳腺癌细胞 DNA 损伤和抗癌活性:一项 TD-DFT 和体外研究。
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-10 DOI: 10.1021/acs.jcim.4c01104
Ranabir Majumder, Shreya Banerjee, Sayan Paul, Saugat Mondal, Madhurima Mandal, Priya Ghosh, Debjit Maity, Anakuthil Anoop, N D Pradeep Singh, Mahitosh Mandal
{"title":"Riboflavin-Induced DNA Damage and Anticancer Activity in Breast Cancer Cells under Visible Light: A TD-DFT and <i>In Vitro</i> Study.","authors":"Ranabir Majumder, Shreya Banerjee, Sayan Paul, Saugat Mondal, Madhurima Mandal, Priya Ghosh, Debjit Maity, Anakuthil Anoop, N D Pradeep Singh, Mahitosh Mandal","doi":"10.1021/acs.jcim.4c01104","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c01104","url":null,"abstract":"<p><p>Targeted treatments for breast cancer that minimize harm to healthy cells are highly sought after. Our study explores the potentiality of riboflavin as a targeted anticancer compound that can be activated by light irradiation. Here, we integrated time-dependent density functional theory (TD-DFT) calculations and an <i>in vitro</i> study under visible light. The TD-DFT calculations revealed that the electronic charge transferred from the DNA base to riboflavin, with the most significant excitation peak occurring within the visible light range. Guided by these insights, an <i>in vitro</i> study was conducted on the breast cancer cell lines MCF-7 and MDA-MB-231. The results revealed substantial growth inhibition in these cell lines when exposed to riboflavin under visible light, with no such impact observed in the absence of light exposure. Interestingly, riboflavin exhibited no/minimal growth-inhibitory effects on the normal cell line L929, irrespective of light conditions. Moreover, through EtBr displacement (<b>DNA</b>-<b>EtBr</b>) and the TUNEL assay, it has been illustrated that, upon exposure to visible light, riboflavin can intercalate within DNA and induce DNA damage. In conclusion, under visible light conditions, riboflavin emerges as a promising candidate with a selective and effective potent anticancer agent against breast cancer while exerting a minimal influence on regular cellular activity.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CageCavityCalc (C3): A Computational Tool for Calculating and Visualizing Cavities in Molecular Cages CageCavityCalc (C3):计算和观察分子笼空腔的计算工具
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-09 DOI: 10.1021/acs.jcim.4c00355
Vicente Martí-Centelles, Tomasz K. Piskorz, Fernanda Duarte
{"title":"CageCavityCalc (C3): A Computational Tool for Calculating and Visualizing Cavities in Molecular Cages","authors":"Vicente Martí-Centelles, Tomasz K. Piskorz, Fernanda Duarte","doi":"10.1021/acs.jcim.4c00355","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00355","url":null,"abstract":"Organic(porous) and metal–organic cages are promising biomimetic platforms with diverse applications spanning recognition, sensing, and catalysis. The key to the emergence of these functions is the presence of well-defined inner cavities capable of binding a wide range of guest molecules and modulating their properties. However, despite the myriad cage architectures currently available, the rational design of structurally diverse and functional cages with specific host–guest properties remains challenging. Efficiently predicting such properties is critical for accelerating the discovery of novel functional cages. Herein, we introduce <i>CageCavityCalc</i> (<i>C</i>3), a Python-based tool for calculating the cavity size of molecular cages. The code is available on GitHub at https://github.com/VicenteMartiCentelles/CageCavityCalc. <i>C3</i> utilizes a novel algorithm that enables the rapid calculation of cavity sizes for a wide range of molecular structures and porous systems. Moreover, <i>C</i>3 facilitates easy visualization of the computed cavity size alongside hydrophobic and electrostatic potentials, providing insights into host–guest interactions within the cage. Furthermore, the calculated cavity can be visualized using widely available visualization software, such as PyMol, VMD, or ChimeraX. To enhance user accessibility, a PyMol plugin has been created, allowing nonspecialists to use this tool without requiring computer programming expertise. We anticipate that the deployment of this computational tool will significantly streamline cage cavity calculations, thereby accelerating the discovery of functional cages.","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
DeltaGzip: Computing Biopolymer-Ligand Binding Affinity via Kolmogorov Complexity and Lossless Compression. DeltaGzip:通过柯尔莫哥洛夫复杂性和无损压缩计算生物聚合物配体结合亲和力
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-09 DOI: 10.1021/acs.jcim.4c00461
Tao Liu, Lena Simine
{"title":"DeltaGzip: Computing Biopolymer-Ligand Binding Affinity via Kolmogorov Complexity and Lossless Compression.","authors":"Tao Liu, Lena Simine","doi":"10.1021/acs.jcim.4c00461","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00461","url":null,"abstract":"<p><p>The design of biosequences for biosensing and therapeutics is a challenging multistep search and optimization task. In principle, computational modeling may speed up the design process by virtual screening of sequences based on their binding affinities to target molecules. However, in practice, existing machine-learned models trained to predict binding affinities lack the flexibility with respect to reaction conditions, and molecular dynamics simulations that can incorporate reaction conditions suffer from high computational costs. Here, we describe a computational approach called DeltaGzip that evaluates the free energy of binding in biopolymer-ligand complexes from ultrashort equilibrium molecular dynamics simulations. The entropy of binding is evaluated using the Kolmogorov complexity definition of entropy and approximated using a lossless compression algorithm, Gzip. We benchmark the method on a well-studied data set of protein-ligand complexes comparing the predictions of DeltaGzip to the free energies of binding obtained using Jarzynski equality and experimental measurements.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141557282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
AttenGpKa: A Universal Predictor of Solvation Acidity Using Graph Neural Network and Molecular Topology. AttenGpKa:利用图神经网络和分子拓扑学的溶解酸度通用预测器
IF 5.6 2区 化学
Journal of Chemical Information and Modeling Pub Date : 2024-07-09 DOI: 10.1021/acs.jcim.4c00449
Hongle An, Xuyang Liu, Wensheng Cai, Xueguang Shao
{"title":"AttenGpKa: A Universal Predictor of Solvation Acidity Using Graph Neural Network and Molecular Topology.","authors":"Hongle An, Xuyang Liu, Wensheng Cai, Xueguang Shao","doi":"10.1021/acs.jcim.4c00449","DOIUrl":"https://doi.org/10.1021/acs.jcim.4c00449","url":null,"abstract":"<p><p>Rapid and accurate calculation of acid dissociation constant (p<i>K</i><sub>a</sub>) is crucial for designing chemical synthesis routes, optimizing catalysts, and predicting chemical behavior. Despite recent progress in machine learning, predicting solvation acidity, especially in nonaqueous solvents, remains challenging due to limited experimental data. This challenge arises from treating experimental values in different solvents as distinct data domains and modeling them separately. In this work, we treat both the solutes and solvents equally from a perspective of molecular topology and propose a highly universal framework called AttenGpKa for predicting solvation acidity. AttenGpKa is trained using 26,522 experimental p<i>K</i><sub>a</sub> values from 60 pure and mixed solvents in the <i>i</i>BonD database. As a result, our model can simultaneously predict the p<i>K</i><sub>a</sub> values of a compound in various solvents, including pure water, pure nonaqueous, and mixed solvents. AttenGpKa achieves universality by using graph neural networks and attention mechanisms to learn complex effects within solute and solvent molecules. Furthermore, encodings of both solute and solvent molecules are adaptively fused to simulate the influence of the solvent on acid dissociation. AttenGpKa demonstrates robust generalization in extensive validations. The interpretability studies further indicate that our model has effectively learnt electronic and solvent effects. A free-to-use software is provided to facilitate the use of AttenGpKa for p<i>K</i><sub>a</sub> prediction.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141561962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信