bioRxiv : the preprint server for biology最新文献_第10页

Osmotic stress triggers fast and reversible PMF collapse in Escherichia coli. 渗透应激触发快速和可逆的PMF在大肠杆菌崩溃。

bioRxiv : the preprint server for biology Pub Date : 2025-09-28 DOI: 10.1101/2025.09.25.678644

Luis Meneses, Eric M Dudebout, Sophia Belser, Jinming Yang, Navish Wadhwa

{"title":"Osmotic stress triggers fast and reversible PMF collapse in Escherichia coli.","authors":"Luis Meneses, Eric M Dudebout, Sophia Belser, Jinming Yang, Navish Wadhwa","doi":"10.1101/2025.09.25.678644","DOIUrl":"10.1101/2025.09.25.678644","url":null,"abstract":"Environmental stressors routinely impact bacteria and affect their physiology. Among the most important physiological parameters is the proton motive force (PMF), that powers vital cellular processes and molecular machines. Measuring how PMF responds to environmental stress in real time requires tools that capture rapid physiological changes with high temporal resolution. Here, we use the bacterial flagella motor as an in vivo voltmeter to probe PMF dynamics during hyperosmotic shock. Because motor rotation frequency scales linearly with PMF, this approach enables single-cell electrophysiology with high temporal resolution. We find that hyperosmotic stress causes a rapid and reversible loss of PMF in Escherichia coli, independent of the osmolyte used or the presence of potassium ions. We corroborate these findings by using the Nernstian dye, tetramethyl rhodamine methyl ester (TMRM), showing that hyperosmotic shock leads to membrane depolarization. Together, our results highlight the efficacy of the flagellar motor as powerful tool for probing bacterial electrophysiology and reveal that hyperosmotic stress directly disrupts cellular energetics in addition to its mechanical effects.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MRAP2 potentiates GPCR signaling by conserved mechanisms that are disrupted by obesity-associated genetic variants. MRAP2通过被肥胖相关的遗传变异破坏的保守机制增强GPCR信号。

bioRxiv : the preprint server for biology Pub Date : 2025-09-28 DOI: 10.1101/2025.09.26.678709

Aqfan Jamaluddin, Rachael A Wyatt, Johannes Broichhagen, Joshua Levitz, Caroline M Gorvin

{"title":"MRAP2 potentiates GPCR signaling by conserved mechanisms that are disrupted by obesity-associated genetic variants.","authors":"Aqfan Jamaluddin, Rachael A Wyatt, Johannes Broichhagen, Joshua Levitz, Caroline M Gorvin","doi":"10.1101/2025.09.26.678709","DOIUrl":"10.1101/2025.09.26.678709","url":null,"abstract":"Accessory proteins such as members of the melanocortin-2 receptor accessory protein family (MRAP) have been described to interact with and regulate the signaling of diverse G protein-coupled receptors (GPCRs), however, surprisingly little is known about the mechanisms by which they mediate these effects. MRAP2 modifies signaling of three distinct GPCRs, melanocortin receptor 4 (MC4R), MC3R and the ghrelin receptor (GHSR), which each play essential roles in appetite regulation. Human mutations in MRAP2 cause obesity with hyperglycaemia and hypertension, suggesting that its regulation of GPCRs is critical for maintaining metabolic homeostasis. However, the nature of MRAP2/GPCR complexes and whether there are shared mechanisms for complex assembly, critical structural regions or consistent effects on receptor signaling and trafficking remains unknown. Here we showed all three GPCRs preferentially interact with MRAP2 as 1:1 complexes and that MRAP2 binding disrupts GPCR homodimerization. MRAP2 interacts with the same receptor transmembrane regions to promote GPCR signaling, and the accessory protein impairs β-arrestin-2 recruitment to prolong signaling and delay internalization. Deletion of the cytoplasmic region of MRAP2 impairs GPCR signaling by modulating receptor constitutive activity. Genetic variants in MRAP2 associated with overweight or obesity modulate the constitutive activity of all three GPCRs. Thus, MRAP2 regulates GPCR function using shared molecular mechanisms and these studies provide further evidence of the importance of GHSR constitutive activity.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

vcfsim: flexible simulation of all-sites VCFs with missing data. vcfsim：灵活模拟缺失数据的全站点vcf。

bioRxiv : the preprint server for biology Pub Date : 2025-09-28 DOI: 10.1101/2025.01.29.635540

Paimon Goulart, Kieran Samuk

{"title":"vcfsim: flexible simulation of all-sites VCFs with missing data.","authors":"Paimon Goulart, Kieran Samuk","doi":"10.1101/2025.01.29.635540","DOIUrl":"10.1101/2025.01.29.635540","url":null,"abstract":"Background |: VCFs are the most widely used data format for encoding genetic variation. By design, standard VCFs do not include data from sites where all individuals are homozygous for the reference allele (\"invariant sites\") and thus do not differentiate these from sites where data are completely missing. However, missing data are a key feature of biological datasets across all domains of genomics, and many recent studies have shown that missing data can introduce a variety of statistical biases in the estimation of key population genetic parameters. A solution to this limitation is to include invariant sites in a standard VCF, creating an \"all-sites VCF\", exposing missing and invariant sites explicitly. One hurdle to the wider adoption of all-sites VCFs is a reliable parameterized simulation framework for generating biologically realistic all-sites VCFs.Results |: Here, we introduce an open-source command line tool, vcfsim, that interfaces with the popular coalescent simulation platform msprime and provides convenience functions for simulating all-sites VCFs with variable levels of ploidy and missing data. We show that the post-processed VCFs generated using vcfsim align precisely with population genetic expectations (i.e. are statistically identical to raw msprime output), accurately introduce missing data, and permit the simulation of data with varying ploidy levels, including the simulation of intraindividual ploidy variation (e.g. heterogametic sex chromosomes) and population structures.Conclusions |: Our results vcfsim is a useful and easy-to-use tool for the benchmarking of new software tools, performing population genetic inference, training of machine learning models, and the exploration of the effects of missing data in genomics data sets.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Using Propensity Score Matching to Control for MRI Scan Quality. 用倾向评分匹配控制MRI扫描质量。

bioRxiv : the preprint server for biology Pub Date : 2025-09-28 DOI: 10.1101/2025.09.26.678901

Veronica J Cramm, Tyler M Call, John A E Anderson

{"title":"Using Propensity Score Matching to Control for MRI Scan Quality.","authors":"Veronica J Cramm, Tyler M Call, John A E Anderson","doi":"10.1101/2025.09.26.678901","DOIUrl":"10.1101/2025.09.26.678901","url":null,"abstract":"Movement during MRI scanning complicates distinguishing between the different tissues in the brain (e.g., grey and white matter). Standard practice excludes scans based on researcher-determined visual quality thresholds. Unfortunately, children, elderly, and clinical populations are shown to move more, resulting in higher exclusion rates. This disproportionate exclusion creates systematic bias in the literature and makes research findings less generalizable. Furthermore, the artifacts caused by motion are demonstrated to continue to confound data, even after visual quality control has occurred. We aimed to minimize the confounding factor of systematic group differences in movement. To achieve this, we used a post-scanning statistical technique called propensity score matching (PSM) that matches control and patient populations on scan quality metrics, leading to more comparable groups, greater inclusion, and more generalizable results. We found that PSM can attenuate significant differences in scan quality between groups while allowing for greater sample diversity than standard exclusion protocols. Crucially, using PSM can also alter the results of neuroimaging-based analyses. Using three datasets (total n = 1536), we compared voxel based morphometry analyses based on different quality control protocols. In particular, we observed discrepant results between PSM and strict threshold exclusion, with PSM magnifying some regional group differences and diminishing others. Overall, PSM is a customizable way to mitigate the impact of confounds in neuroimaging research and a powerful method to help distinguish true effects from artifacts.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lactate promotes longevity through redox-driven lipid remodeling in Caenorhabditis elegans. 乳酸通过氧化还原驱动的脂质重塑促进秀丽隐杆线虫的寿命。

bioRxiv : the preprint server for biology Pub Date : 2025-09-28 DOI: 10.1101/2025.09.25.678523

Arnaud Tauffenberger, Payton J Netherland, Hubert Fiumelli, Joshua D Meisel, Frank C Schroeder, Pierre Magistretti

{"title":"Lactate promotes longevity through redox-driven lipid remodeling in Caenorhabditis elegans.","authors":"Arnaud Tauffenberger, Payton J Netherland, Hubert Fiumelli, Joshua D Meisel, Frank C Schroeder, Pierre Magistretti","doi":"10.1101/2025.09.25.678523","DOIUrl":"10.1101/2025.09.25.678523","url":null,"abstract":"Lactate has emerged as a key metabolite involved in multiple physiological processes, including memory formation, immune response regulation, and muscle biogenesis. However, its role in aging and cellular protection remains unclear. Here, we show that lactate promotes longevity in C. elegans through a mechanism that requires early-life intervention, indicating a hormetic priming effect. This pro-longevity action depends on its metabolic conversion via LDH-1 and NADH, which drives redox-dependent metabolic reprogramming. Multi-omics approaches revealed that lactate induces early-stage metabolic adaptations, with a strong modulation of lipid metabolism, followed by late-life transcriptional remodeling. These shifts are characterized by enhanced stress response pathways and suppression of energy-associated metabolic processes. Our genetic screening identified sir-2.1/SIRT1 and rict-1/RICTOR as essential for lactate-mediated lifespan extension. Our findings establish lactate as a pro-longevity metabolite that couples redox signaling with lipid remodeling and nutrient-sensing pathways. This work advances our understanding of lactate's dual role as a metabolic intermediary and geroprotector signaling molecule, offering insights into therapeutic strategies for age-related metabolic disorders.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Local thalamic interneurons drive spindle termination and enable sleep-dependent learning. 局部丘脑中间神经元驱动纺锤体终止并使睡眠依赖学习成为可能。

bioRxiv : the preprint server for biology Pub Date : 2025-09-27 DOI: 10.1101/2025.09.26.678870

Jane Simko, Tamina Keira Ramirez, Caryn Martin, Sally Leung, Eleni A Sung, Christopher D Makinson

{"title":"Local thalamic interneurons drive spindle termination and enable sleep-dependent learning.","authors":"Jane Simko, Tamina Keira Ramirez, Caryn Martin, Sally Leung, Eleni A Sung, Christopher D Makinson","doi":"10.1101/2025.09.26.678870","DOIUrl":"https://doi.org/10.1101/2025.09.26.678870","url":null,"abstract":"The thalamus is central to fundamental brain functions including sensation, attention, and sleep through the precise generation and regulation of neuronal ensemble oscillatory activity. Sensory thalamic circuits are considered feedforward structures, lacking lateral connectivity, while recurrence in the network is mediated by interactions with inhibitory neurons of the thalamic reticular nucleus. Here, we define previously uncharacterized functional roles of local thalamic interneurons, a component of the sensory thalamus whose function has remained unexplored. We demonstrate that local interneuron activation induces rebound oscillations in thalamocortical relay neurons ex vivo and neocortical spindles in vivo , while their inhibition increases spindle occurrence, overall spindle duration and impairs sensory learning. Our findings reveal that local thalamic interneurons have shared and complementary functions to those of thalamic reticular neurons and are required for proper spindle formation and sleep-dependent learning. Together, this work establishes an important neural substrate of thalamocortical circuit function.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual Targeting of IKKβ and NR4A1 for AML Therapy. 双重靶向IKKβ和NR4A1治疗AML。

bioRxiv : the preprint server for biology Pub Date : 2025-09-27 DOI: 10.1101/2025.09.24.678355

Chandra K Maharjan, Yi Liu, Yufeng Xiao, Bristy R Podder, Tyler H Montgomery, Lei Wang, Myung-Chul Kim, Zeng Jin, Seyedehalaleh Anvar, Alexandra M Stevens, Ryan Kolb, Chen Zhao, Zhijian Qian, Jatinder Lamba, Guangrong Zheng, Weizhou Zhang

{"title":"Dual Targeting of IKKβ and NR4A1 for AML Therapy.","authors":"Chandra K Maharjan, Yi Liu, Yufeng Xiao, Bristy R Podder, Tyler H Montgomery, Lei Wang, Myung-Chul Kim, Zeng Jin, Seyedehalaleh Anvar, Alexandra M Stevens, Ryan Kolb, Chen Zhao, Zhijian Qian, Jatinder Lamba, Guangrong Zheng, Weizhou Zhang","doi":"10.1101/2025.09.24.678355","DOIUrl":"https://doi.org/10.1101/2025.09.24.678355","url":null,"abstract":"Acute myeloid leukemia (AML) is a common and aggressive blood cancer with the highest lethality rate among all leukemia subtypes. The cure rate of available therapeutic options is very low, underscoring an urgent need to develop novel and effective AML therapeutics. Here we identify IKKβ and NR4A1 as two closely related drivers of AML progression and develop a proteolysis targeting chimera (PROTAC) drug that has dual degradation activity against IKKβ and NR4A1. IKKβ and its downstream nuclear factor-κB (NF-κB) signaling are aberrantly activated in around 40% AML patients. However, nearly all IKKβ inhibitors have failed prior clinical trials due to their serious side effects such as neutrophilia and systematic inflammation. As opposed to the previously reported tumor suppressive role in AML, we found that NR4A1 promotes AML pathogenesis in a context-dependent manner. Here we designed, synthesized, and validated several celastrol-based PROTACs, with one lead compound A9 that effectively kills several AML cell lines and primary human AML cells via the degradation of IKKβ and NR4A1. At the mechanistic level, A9 degrades both targets through cereblon (CRBN) E3 ligase-mediated proteasomal system by forming ternary complexes with the target proteins and CRBN. More importantly, A9 attenuates AML disease progression in a clinically relevant KMT2A::MLLT3 mouse model and doesn't induce neutrophilia in vivo - a common side effect of IKKβ inhibitors. Our results reveal a potentially novel strategy to treat intractable and aggressive AMLs in the clinic.Key points: IKKβ and NR4A1 are clinically relevant mediators of AML pathogenesis.A novel celastrol-based PROTAC can effectively degrade both IKKβ and NR4A1 to disrupt AML pathogenesis.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vitro and in vivo derived macrophages occupy distinct phenotypic states. 体外和体内衍生的巨噬细胞具有不同的表型状态。

bioRxiv : the preprint server for biology Pub Date : 2025-09-27 DOI: 10.1101/2025.09.20.677495

Stéphane Chevrier, Vito R T Zanotelli, Daniel Schulz, Mark D Robinson, Laurie Ailles, Michel A S Jewett, Craig Gedye, Bernhard Reis, Bernd Bodenmiller

{"title":"In vitro and in vivo derived macrophages occupy distinct phenotypic states.","authors":"Stéphane Chevrier, Vito R T Zanotelli, Daniel Schulz, Mark D Robinson, Laurie Ailles, Michel A S Jewett, Craig Gedye, Bernhard Reis, Bernd Bodenmiller","doi":"10.1101/2025.09.20.677495","DOIUrl":"10.1101/2025.09.20.677495","url":null,"abstract":"Monocyte-derived macrophages (MDMs) are widely used to model human macrophage biology in vitro and standardized polarization conditions were proposed to recapitulate the different macrophage activation states. Although surface markers specific for distinct MDM populations have been identified, a systematic analysis of surface marker expression on these consensus MDM populations has not previously been reported. Here, we use mass cytometry to perform an in-depth characterization of MDM surface profiles and determine how these markers evolve with time. We also compared the phenotypes found in vitro with patient-derived tumor-associated macrophages (TAMs) and found that although MDMs and TAMs shared most markers investigated, the cell-surface signatures markedly differed in terms of expression levels and combinations. Our high-dimensional, single-cell analyses clarifies the surface expression profile of the core in vitro differentiated macrophage populations and highlights some limitations of the in vitro system to represent the complexity of in vivo polarized tumor-associated macrophage phenotypes. These findings provide new opportunities to improve the models used to study macrophage biology and give a pathway to improve our understanding of the in vivo complexity of these systems.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evolution of parasitism-related traits in nematodes. 线虫寄生相关性状的进化。

bioRxiv : the preprint server for biology Pub Date : 2025-09-27 DOI: 10.1101/2025.09.26.678730

Chieh-Hsiang Tan, Hillel T Schwartz, Nathan Y Rodak, Paul W Sternberg

{"title":"Evolution of parasitism-related traits in nematodes.","authors":"Chieh-Hsiang Tan, Hillel T Schwartz, Nathan Y Rodak, Paul W Sternberg","doi":"10.1101/2025.09.26.678730","DOIUrl":"10.1101/2025.09.26.678730","url":null,"abstract":"The abundant resources provided by the host provide an evolutionary rationale for parasitism and drive the metabolic and developmental divergence of parasitic and free-living animals. Two evolutionally distant nematode genera, Steinernema and Heterorhabditis, independently evolved an entomopathogenic lifestyle, in which they invade insects and kill them with the assistance of specifically associated symbiotic pathogenic bacteria. It had been generally assumed that the worm, being a bacterivore, feeds on its symbiotic bacteria, which rapidly reproduce while consuming the insect host. The evolutionary adaptations of entomopathogenic nematodes to a parasitic lifestyle developmentally, and the symbiotic relationships of entomopathogenicity, remain largely unknown. We developed an axenic culture medium that allows for robust and sustained growth of Steinernema hermaphroditum, allowing finite control of nutrients available to the nematodes. We found that, uniquely among nematodes tested, the hatchlings of S. hermaphroditum cannot endure in a nutrient-poor environment; this ability is impaired but still present in Heterorhabditis bacteriophora. Similarly, the ability to forage for food is completely lost in H. bacteriophora hatchlings and severely compromised in S. hermaphroditum. We reasoned that these traits were lost because they are unnecessary to obligate parasites that always hatch in a resource-rich host. We further found that Steinernema and, to a limited extent, Heterorhabditis nematodes can successfully invade, develop, and reproduce inside a living insect host independent of their symbiotic bacteria, apparently feeding on the hemolymph, and emerge carrying bacteria found within, explaining the evolutionary origins of entomopathogenic nematodes.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modeling protein-small molecule conformational ensembles with PLACER. 利用 ChemNet 建立蛋白质-小分子构象组合模型。

bioRxiv : the preprint server for biology Pub Date : 2025-09-27 DOI: 10.1101/2024.09.25.614868

Ivan Anishchenko, Yakov Kipnis, Indrek Kalvet, Guangfeng Zhou, Rohith Krishna, Samuel J Pellock, Anna Lauko, Gyu Rie Lee, Linna An, Justas Dauparas, Frank DiMaio, David Baker

{"title":"Modeling protein-small molecule conformational ensembles with PLACER.","authors":"Ivan Anishchenko, Yakov Kipnis, Indrek Kalvet, Guangfeng Zhou, Rohith Krishna, Samuel J Pellock, Anna Lauko, Gyu Rie Lee, Linna An, Justas Dauparas, Frank DiMaio, David Baker","doi":"10.1101/2024.09.25.614868","DOIUrl":"10.1101/2024.09.25.614868","url":null,"abstract":"Modeling the conformational heterogeneity of protein-small molecule interactions is important for understanding natural systems and evaluating designed systems, but remains an outstanding challenge. We reasoned that while residue level descriptions of biomolecules are efficient for de novo structure prediction, for probing heterogeneity of interactions with small molecules in the folded state an entirely atomic level description could have advantages in speed and generality. We developed a graph neural network called PLACER (Protein-Ligand Atomistic Conformational Ensemble Resolver) trained to recapitulate correct atomic positions from partially corrupted input structures from the Cambridge Structural Database and the Protein Data Bank; the nodes of the graph are the atoms in the system. PLACER accurately generates structures of diverse organic small molecules given knowledge of their atom composition and bonding, and given a description of the larger protein context, builds up structures of small molecules and protein side chains for protein-small molecule docking. Because PLACER is rapid and stochastic, ensembles of predictions can be readily generated to map conformational heterogeneity. In enzyme design efforts described here and elsewhere, we find that using PLACER to assess the accuracy and pre-organization of the designed active sites results in higher success rates and higher activities; we obtain a preorganized retroaldolase with a k cat/K M of 11000 M-1min-1, considerably higher than any pre-deep learning design for this reaction. We anticipate that PLACER will be widely useful for rapidly generating conformational ensembles of small molecule and small molecule-protein systems, and for designing higher activity preorganized enzymes.","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142396813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0