QRB Discovery最新文献_第3页

Probing DNA melting behaviour under vibrational strong coupling. 探测DNA在振动强耦合下的熔化行为。

QRB Discovery Pub Date : 2025-03-10 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.5

Weijian Tao, Fatma Mihoubi, Bianca Patrahau, Claudia Bonfio, Bengt Nordén, Thomas W Ebbesen

引用次数: 0

Modeling for understanding and engineering metabolism. 为理解和工程代谢建模。

QRB Discovery Pub Date : 2025-02-18 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.1

Jens Nielsen, Dina Petranovic

{"title":"Modeling for understanding and engineering metabolism.","authors":"Jens Nielsen, Dina Petranovic","doi":"10.1017/qrd.2025.1","DOIUrl":"10.1017/qrd.2025.1","url":null,"abstract":"Metabolism is at the core of all functions of living cells as it provides Gibbs free energy and building blocks for synthesis of macromolecules, which are necessary for structures, growth, and proliferation. Metabolism is a complex network composed of thousands of reactions catalyzed by enzymes involving many co-factors and metabolites. Traditionally it has been difficult to study metabolism as a whole network and most traditional efforts were therefore focused on specific metabolic pathways, enzymes, and metabolites. By using engineering principles of mathematical modeling to analyze and study metabolism, as well as engineer it, that is, design and build, new metabolic features, it is possible to gain many new fundamental insights as well as applications in biotechnology. Here, we present the history and basic principles of engineering metabolism, as well as the newest developments in the field. We are using examples of applications in: (1) production of protein pharmaceuticals and chemicals; (2) basic studies of metabolism; and (3) impacting health care. We will end by discussing how engineering metabolism can benefit from advances in artificial intelligence (AI)-based models.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e11"},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606214","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

Reduced protein solubility - cause or consequence in amyloid disease? 蛋白溶解度降低——淀粉样蛋白病的原因或后果？

QRB Discovery Pub Date : 2025-02-17 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2024.12

Max Lindberg, Jing Hu, Emma Sparr, Sara Linse

引用次数: 0

Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog. 人线粒体呼吸整体膜巨复合物的结构生物信息学研究及其AlphaFold3预测水溶性QTY巨复合物类似物。

QRB Discovery Pub Date : 2025-02-05 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.2

Edward Chen, Shuguang Zhang

{"title":"Structural bioinformatic study of human mitochondrial respiratory integral membrane megacomplex and its AlphaFold3 predicted water-soluble QTY megacomplex analog.","authors":"Edward Chen, Shuguang Zhang","doi":"10.1017/qrd.2025.2","DOIUrl":"10.1017/qrd.2025.2","url":null,"abstract":"Human mitochondrial Complex I is one of the largest multi-subunit membrane protein megacomplexes, which plays a critical role in oxidative phosphorylation and ATP production. It is also involved in many neurodegenerative diseases. However, studying its structure and the mechanisms underlying proton translocation remains challenging due to the hydrophobic nature of its transmembrane parts. In this structural bioinformatic study, we used the QTY code to reduce the hydrophobicity of megacomplex I, while preserving its structure and function. We carried out the structural bioinformatics analysis of 20 key enzymes in the integral membrane parts. We compare their native structure, experimentally determined using Cryo-electron microscopy (CryoEM), with their water-soluble QTY analogs predicted using AlphaFold 3. Leveraging AlphaFold 3's advanced capabilities in predicting protein-protein complex interactions, we further explore whether the QTY-code integral membrane proteins maintain their protein-protein interactions necessary to form the functional megacomplex. Our structural bioinformatics analysis not only demonstrates the feasibility of engineering water-soluble integral membrane proteins using the QTY code, but also highlights the potential to use the water-soluble membrane protein QTY analogs as soluble antigens for discovery of therapeutic monoclonal antibodies, thus offering promising implications for the treatment of various neurodegenerative diseases.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e12"},"PeriodicalIF":0.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754854","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

Protein secondary structure determined from independent and integrated infra-red absorbance and circular dichroism data using the algorithm SELCON. 利用SELCON算法从独立和集成的红外吸光度和圆二色性数据确定蛋白质二级结构。

QRB Discovery Pub Date : 2025-02-03 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.4

Søren Vrønning Hoffmann, Nykola C Jones, Alison Rodger

引用次数: 0

Frontiers in integrative structural modeling of macromolecular assemblies. 大分子组装体综合结构建模的前沿。

QRB Discovery Pub Date : 2025-01-22 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2024.15

Kartik Majila, Shreyas Arvindekar, Muskaan Jindal, Shruthi Viswanath

{"title":"Frontiers in integrative structural modeling of macromolecular assemblies.","authors":"Kartik Majila, Shreyas Arvindekar, Muskaan Jindal, Shruthi Viswanath","doi":"10.1017/qrd.2024.15","DOIUrl":"10.1017/qrd.2024.15","url":null,"abstract":"Integrative modeling enables structure determination for large macromolecular assemblies by combining data from multiple experiments with theoretical and computational predictions. Recent advancements in AI-based structure prediction and cryo electron-microscopy have sparked renewed enthusiasm for integrative modeling; structures from AI-based methods can be integrated with in situ maps to characterize large assemblies. This approach previously allowed us and others to determine the architectures of diverse macromolecular assemblies, such as nuclear pore complexes, chromatin remodelers, and cell-cell junctions. Experimental data spanning several scales was used in these studies, ranging from high-resolution data, such as X-ray crystallography and AlphaFold structure, to low-resolution data, such as cryo-electron tomography maps and data from co-immunoprecipitation experiments. Two recurrent modeling challenges emerged across a range of studies. First, these assemblies contained significant fractions of disordered regions, necessitating the development of new methods for modeling disordered regions in the context of ordered regions. Second, methods needed to be developed to utilize the information from cryo-electron tomography, a timely challenge as structural biology is increasingly moving towards in situ characterization. Here, we recapitulate recent developments in the modeling of disordered proteins and the analysis of cryo-electron tomography data and highlight other opportunities for method development in the context of integrative modeling.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e3"},"PeriodicalIF":0.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411147","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

Integrin force loading rate in mechanobiology: From model to molecular measurement. 力学生物学中的整合素力加载率：从模型到分子测量。

QRB Discovery Pub Date : 2025-01-16 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2024.28

Hongyuan Zhang, Micah Yang, Seong Ho Kim, Isaac T S Li

{"title":"Integrin force loading rate in mechanobiology: From model to molecular measurement.","authors":"Hongyuan Zhang, Micah Yang, Seong Ho Kim, Isaac T S Li","doi":"10.1017/qrd.2024.28","DOIUrl":"10.1017/qrd.2024.28","url":null,"abstract":"Integrins are critical transmembrane receptors that connect the extracellular matrix (ECM) to the intracellular cytoskeleton, playing a central role in mechanotransduction - the process by which cells convert mechanical stimuli into biochemical signals. The dynamic assembly and disassembly of integrin-mediated adhesions enable cells to adapt continuously to changing mechanical cues, regulating essential processes such as adhesion, migration, and proliferation. In this review, we explore the molecular clutch model as a framework for understanding the dynamics of integrin - ECM interactions, emphasizing the critical importance of force loading rate. We discuss how force loading rate bridges internal actomyosin-generated forces and ECM mechanical properties like stiffness and ligand density, determining whether sufficient force is transmitted to mechanosensitive proteins such as talin. This force transmission leads to talin unfolding and activation of downstream signalling pathways, ultimately influencing cellular responses. We also examine recent advances in single-molecule DNA tension sensors that have enabled direct measurements of integrin loading rates, refining the range to approximately 0.5-4 pN/s. These findings deepen our understanding of force-mediated mechanotransduction and underscore the need for improved sensor designs to overcome current limitations.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e9"},"PeriodicalIF":0.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11950791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754852","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

Diverse single-stranded nucleic acid binding proteins enable both stable protection and rapid exchange required for biological function. 多种单链核酸结合蛋白能够实现生物功能所需的稳定保护和快速交换。

QRB Discovery Pub Date : 2025-01-14 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2024.21

Michael Morse, Ben A Cashen, Ioulia Rouzina, Mark C Williams

{"title":"Diverse single-stranded nucleic acid binding proteins enable both stable protection and rapid exchange required for biological function.","authors":"Michael Morse, Ben A Cashen, Ioulia Rouzina, Mark C Williams","doi":"10.1017/qrd.2024.21","DOIUrl":"10.1017/qrd.2024.21","url":null,"abstract":"Single-stranded nucleic acid (ssNA) binding proteins must both stably protect ssNA transiently exposed during replication and other NA transactions, and also rapidly reorganize and dissociate to allow further NA processing. How these seemingly opposing functions can coexist has been recently elucidated by optical tweezers (OT) experiments that isolate and manipulate single long ssNA molecules to measure conformation in real time. The effective length of an ssNA substrate held at fixed tension is altered upon protein binding, enabling quantification of both the structure and kinetics of protein-NA interactions. When proteins exhibit multiple binding states, however, OT measurements may produce difficult to analyze signals including non-monotonic response to free protein concentration and convolution of multiple fundamental rates. In this review we compare single-molecule experiments with three proteins of vastly different structure and origin that exhibit similar ssNA interactions. These results are consistent with a general model in which protein oligomers containing multiple binding interfaces switch conformations to adjust protein:NA stoichiometry. These characteristics allow a finite number of proteins to protect long ssNA regions by maximizing protein-ssNA contacts while also providing a pathway with reduced energetic barriers to reorganization and eventual protein displacement when these ssNA regions are diminished.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e1"},"PeriodicalIF":0.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411145","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

Unzipping of knotted DNA via nanopore translocation. 通过纳米孔易位解结DNA。

QRB Discovery Pub Date : 2025-01-09 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2024.26

Antonio Suma, Cristian Micheletti

{"title":"Unzipping of knotted DNA via nanopore translocation.","authors":"Antonio Suma, Cristian Micheletti","doi":"10.1017/qrd.2024.26","DOIUrl":"10.1017/qrd.2024.26","url":null,"abstract":"DNA unzipping by nanopore translocation has implications in diverse contexts, from polymer physics to single-molecule manipulation to DNA-enzyme interactions in biological systems. Here we use molecular dynamics simulations and a coarse-grained model of DNA to address the nanopore unzipping of DNA filaments that are knotted. This previously unaddressed problem is motivated by the fact that DNA knots inevitably occur in isolated equilibrated filaments and in vivo. We study how different types of tight knots in the DNA segment just outside the pore impact unzipping at different driving forces. We establish three main results. First, knots do not significantly affect the unzipping process at low forces. However, knotted DNAs unzip more slowly and heterogeneously than unknotted ones at high forces. Finally, we observe that the microscopic origin of the hindrance typically involves two concurrent causes: the topological friction of the DNA chain sliding along its knotted contour and the additional friction originating from the entanglement with the newly unzipped DNA. The results reveal a previously unsuspected complexity of the interplay of DNA topology and unzipping, which should be relevant for interpreting nanopore-based single-molecule unzipping experiments and improving the modeling of DNA transactions in vivo.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e4"},"PeriodicalIF":0.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410754","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

Challenges in observing transcription-translation for bottom-up synthetic biology. 观察自下而上合成生物学转录-翻译的挑战。

QRB Discovery Pub Date : 2025-01-03 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2024.27

Vadim G Bogatyr, Gijs J L Wuite

{"title":"Challenges in observing transcription-translation for bottom-up synthetic biology.","authors":"Vadim G Bogatyr, Gijs J L Wuite","doi":"10.1017/qrd.2024.27","DOIUrl":"10.1017/qrd.2024.27","url":null,"abstract":"Synthetic biology aims to create a viable synthetic cell. However, to achieve this goal, it is essential first to gain a profound understanding of the cellular systems used to build that cell, how to reconstitute those systems in the compartments, and how to track their function. Transcription and translation are two vital cellular systems responsible for the production of RNA and, consequently, proteins, without which the cell would not be able to maintain itself or fulfill its functions. This review discusses in detail how the Protein synthesis Using Recombinant Element (PURE) system and cell lysate are used to reconstitute transcription-translation in vitro. Furthermore, it examines how these systems can be encapsulated in GUVs using the existing methods. It also assesses approaches available to image transcription and translation with a diverse arsenal of fluorescence microscopy techniques and a broad collection of probes developed in recent decades. Finally, it highlights solutions for the challenge ahead, namely the decoupling of the two systems in PURE, and discusses the prospects of synthetic biology in the modern world.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e5"},"PeriodicalIF":0.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411085","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