QRB Discovery最新文献_第2页

Thermodynamic control of gene regulation. 基因调控的热力学控制。

QRB Discovery Pub Date : 2025-09-26 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.10013

James W Wells, Tigran V Chalikian

{"title":"Thermodynamic control of gene regulation.","authors":"James W Wells, Tigran V Chalikian","doi":"10.1017/qrd.2025.10013","DOIUrl":"10.1017/qrd.2025.10013","url":null,"abstract":"G-quadruplexes and i-motifs are non-canonical secondary structures of DNA that act as conformational switches in controlling genomic events. Within the genome, G- and C-rich sequences with the potential to fold into G-quadruplexes and i-motifs are overrepresented in important regulatory domains, including, but not limited to, the promoter regions of oncogenes. We previously have shown that some promoter sequences can adopt coexisting duplex, G-quadruplex, i-motif, and coiled conformations; moreover, their distribution can be modelled as a dynamic equilibrium in which the fractional population of each conformation is determined by the sequence and local conditions. On that basis, we proposed a hypothesis in which the level of expression of a gene with G- and C-rich sequences in the promoter is regulated thermodynamically by fine-tuning the duplex-to-G-quadruplex ratio, with the G-quadruplex modulating RNA polymerase activity. Any deviation from the evolutionarily tuned, gene-specific distribution of conformers, such as might result from mutations in the promoter or a change in cellular conditions, may lead to under- or overexpression of the gene and pathological consequences. We now expand on this hypothesis in the context of supporting evidence from molecular and cellular studies and from biophysico-chemical investigations of oligomeric DNA. Thermodynamic control of transcription implies that G-quadruplex and i-motif structures in the genome form as thermodynamically stable conformers in competition with the duplex conformation. That is in addition to their recognized formation as kinetically trapped, metastable states within domains of single-stranded DNA, such as a transcription bubble or R-loop, that are opened in a prior cellular event.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e24"},"PeriodicalIF":0.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12554805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145393754","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

On the possibility of carbon-free heteropolymers on Venus: a computational astrobiology study. 关于金星上无碳杂聚物的可能性：一项计算天体生物学研究。

QRB Discovery Pub Date : 2025-09-25 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.10012

Ishaan Madan, Shekoufeh Arabi Aliabadi, Johanna Huhtasaari, Ebba Matic, Emil Hogedal, Kinga Kamińska, Filip Nilsson, Axel Stark, Fernando Izquierdo-Ruiz, Hilda Sandström, Martin Rahm

{"title":"On the possibility of carbon-free heteropolymers on Venus: a computational astrobiology study.","authors":"Ishaan Madan, Shekoufeh Arabi Aliabadi, Johanna Huhtasaari, Ebba Matic, Emil Hogedal, Kinga Kamińska, Filip Nilsson, Axel Stark, Fernando Izquierdo-Ruiz, Hilda Sandström, Martin Rahm","doi":"10.1017/qrd.2025.10012","DOIUrl":"10.1017/qrd.2025.10012","url":null,"abstract":"This work poses and partially explores an astrobiological hypothesis: might polymeric sulfur and phosphorus-based oxides form heteropolymers in the acidic cloud decks of Venus' atmosphere? Following an introduction to the emerging field of computational astrobiology, we demonstrate the use of quantum chemical methods to evaluate basic properties of a hypothetical carbon-free heteropolymer that might be sourced from feedstock in the Venusian atmosphere. Our modeling indicates that R-substituted polyphosphoric sulfonic ester polymers may form via multiple thermodynamically favorable pathways and exhibit sufficient kinetic stability to persist in the Venusian clouds. Their thermodynamic stability compares favorably to polypeptides, whose formation is slightly thermodynamically unfavored relative to amino acids in most known abiotic conditions. We propose a combined approach of vibrational spectroscopy and mass spectrometry to search for related materials in Venus's atmosphere but note that none of the currently planned missions are well suited for their detection. While predicted Ultraviolet-Visible spectra suggest that the studied polymers are unlikely candidates for Venus's unidentified UV absorbers, the broader possibility of sulfuric acid-based chemistry supporting alternative biochemistries challenges the traditional carbon-centric models of life. We argue that such unconventional lines of inquiry are warranted in the search for life beyond Earth.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e23"},"PeriodicalIF":0.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12554815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145393816","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

A workflow to define structural classes and classify nucleic acids circular dichroism spectra. 定义结构类和分类核酸的工作流程圆二色光谱。

QRB Discovery Pub Date : 2025-09-23 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.10008

Kevin Mosca, Søren Vrønning Hoffmann, Alice Grangier, Frank Wien, Veronique Arluison, Sergio Marco

{"title":"A workflow to define structural classes and classify nucleic acids circular dichroism spectra.","authors":"Kevin Mosca, Søren Vrønning Hoffmann, Alice Grangier, Frank Wien, Veronique Arluison, Sergio Marco","doi":"10.1017/qrd.2025.10008","DOIUrl":"10.1017/qrd.2025.10008","url":null,"abstract":"Circular dichroism (CD) spectroscopy is a widely utilized technique for studying the structures of chiral molecules, including nucleic acids. It is particularly valued for its ability to quickly probe structural changes in these biomolecules. Despite its potential, the prediction of nucleic acid structures by CD has been challenging due to insufficient families' reference spectral data. This study introduces a robust method for defining CD spectra families of nucleic acid structures. We developed an iterative workflow that accurately classifies spectra for nucleic acid structures in solution. Our approach demonstrates high robustness and accuracy in assigning CD spectra to specific nucleic acid folds, facilitating advancements in nucleic acid structure analysis. The algorithm we developed identifies structural classes based on reference spectra, aiding in the assignment of unknown spectra. This method paves the way for creating a comprehensive list of reference spectra for various nucleic acid structures, like those already available for proteins.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e22"},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186911","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

Unraveling the nature of physicochemical and biological processes underlying vesicular exocytotic release events through modeling of amperometric current spikes. 通过模拟安培电流峰值，揭示囊泡胞吐释放事件背后的物理化学和生物过程的本质。

QRB Discovery Pub Date : 2025-07-24 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.10010

Alexander Oleinick, Irina Svir, Christian Amatore

{"title":"Unraveling the nature of physicochemical and biological processes underlying vesicular exocytotic release events through modeling of amperometric current spikes.","authors":"Alexander Oleinick, Irina Svir, Christian Amatore","doi":"10.1017/qrd.2025.10010","DOIUrl":"10.1017/qrd.2025.10010","url":null,"abstract":"This work offers a comprehensive approach to understanding the phenomena underlying vesicular exocytosis, a process involved in vital functions of living organisms such as neuronal and neuroendocrine signaling. The kinetics of release of most neuromediators that modulate these functions in various ways can be efficiently monitored using single-cell amperometry (SCA). Indeed, SCA at ultramicro- or nanoelectrodes provides the necessary temporal, flux, and nanoscale resolution to accurately report on the shape and intensity of single exocytotic spikes. Rather than characterizing amperometric spikes using standard descriptive parameters (e.g., amplitude and half-width), however, this study summarizes a modeling approach based on the underlying biology and physical chemistry of single exocytotic events. This approach provides deeper insights into intravesicular phenomena that control vesicular release dynamics. The ensuing model's intrinsic parsimony makes it computationally efficient and friendly, enabling the processing of large amperometric traces to gain statistically significant insights.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e21"},"PeriodicalIF":0.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12418276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041541","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

A structural and functional bioinformatics study of QTY-designed retinylidene proteins. qty设计的视黄醛蛋白的结构和功能生物信息学研究。

QRB Discovery Pub Date : 2025-07-14 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.10009

Siqi Pan

{"title":"A structural and functional bioinformatics study of QTY-designed retinylidene proteins.","authors":"Siqi Pan","doi":"10.1017/qrd.2025.10009","DOIUrl":"10.1017/qrd.2025.10009","url":null,"abstract":"Retinylidene proteins are retinal-binding light-sensitive proteins found in organisms ranging from microbes to human. Microbial opsins have been utilized in optogenetics, while animal opsins are essential for vision and light-dependent metabolic functions. However, retinylidene proteins have hydrophobic transmembrane (TM) domains, which makes them challenging to study. In this structural and functional bioinformatics study, I use the QTY (glutamine, threonine, tyrosine) code to design water-soluble QTY analogues of retinylidene proteins, including nine human and three microbial opsins. I provide superpositions of the AlphaFold3-predicted hydrophobic native proteins and their water-soluble QTY analogues, and experimentally determined structures when available. I also provide a comparison of surface hydrophobicity of the variants. Despite significant changes to the protein sequence (35.53-50.24% in the TM domain), protein characteristics and structures are well preserved. Furthermore, I run molecular dynamics (MD) simulations of native and QTY-designed OPN2 (rhodopsin) and analyze their response to the isomerization of 11-cis-retinal to all-trans-retinal. The results show that the QTY analogue has similar functional behavior to the native protein. The findings of this study indicate that the QTY code can be used as a robust tool to design water-soluble retinylidene proteins. These have potential applications in protein studies, therapeutic treatments, and bioengineering.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e20"},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144972119","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

The dawn of biophysical representations in computational immunology. 计算免疫学中生物物理表征的曙光。

QRB Discovery Pub Date : 2025-05-28 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.7

Eric Wilson, Akshansh Kaushik, Soumya Dutta, Abhishek Singharoy

引用次数: 0

High-throughput single-molecule nanofluidic studies on B. subtilis Rok protein interaction with DNA. 枯草芽孢杆菌Rok蛋白与DNA相互作用的高通量单分子纳米流体研究。

QRB Discovery Pub Date : 2025-05-19 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.10007

Evgeniya Pavlova, Radhika Nambannor Kunnath, Bert van Erp, Albertas Dvirnas, Sriram Kk, Remus T Dame, Fredrik Westerlund

{"title":"High-throughput single-molecule nanofluidic studies on B. subtilis Rok protein interaction with DNA.","authors":"Evgeniya Pavlova, Radhika Nambannor Kunnath, Bert van Erp, Albertas Dvirnas, Sriram Kk, Remus T Dame, Fredrik Westerlund","doi":"10.1017/qrd.2025.10007","DOIUrl":"10.1017/qrd.2025.10007","url":null,"abstract":"Single-molecule methods offer powerful insights into DNA-protein interactions at the individual DNA molecule level. We developed an automated, high-throughput nanofluidic imaging platform to characterize DNA-protein complexes in solution. The platform uses a nanofluidic chip with 10 sets of nanochannels where thousands of DNA molecules can be simultaneously analyzed in different conditions. Using this approach, we investigate Rok, a multifunctional Bacillus subtilis protein involved in genome organization and transcription regulation. Our findings confirm the DNA-condensing activity of Rok, likely attributed to its ability to bridge distant DNA segments. Additionally, Rok promotes the hybridization of 12 base complementary single-stranded DNA overhangs, suggesting a potential role in homology search during recombination. Rok also displays sequence-selective binding, preferentially associating with adenine and thymine-rich (AT-rich) DNA regions. To explore the structural features of Rok underlying these activities and test our nanofluidic system further, we compare wild-type Rok with two variants: ∆Rok, lacking the neutral part of the internal linker, and sRok, a naturally occurring variant without the linker. This comparison highlights the role of the linker in hybridization, i.e., interaction with single-stranded DNA. Together, these findings enhance our understanding of Rok-mediated DNA dynamics and establish single-molecule nanofluidics as a powerful tool for high-throughput studies of DNA-protein interactions.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e17"},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12231313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585062","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

Insights on the effect of macromolecular crowding on transcription and its regulation. 大分子拥挤对转录及其调控的影响。

QRB Discovery Pub Date : 2025-04-03 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.8

Wenxuan Xu, Dylan Collette, Jin Qian, Laura Finzi, David Dunlap

{"title":"Insights on the effect of macromolecular crowding on transcription and its regulation.","authors":"Wenxuan Xu, Dylan Collette, Jin Qian, Laura Finzi, David Dunlap","doi":"10.1017/qrd.2025.8","DOIUrl":"10.1017/qrd.2025.8","url":null,"abstract":"Transcription of DNA into RNA is a fundamental cellular process upon which life depends. It is tightly regulated in several different ways, and among the most important mechanisms are protein-induced topological changes in DNA such as looping. In vivo neither transcription, nor protein-induced looping dynamics exhibited by individual molecules are easily monitored. In vitro single-molecule approaches do offer that possibility, but assays are conducted in rarefied, saline buffer conditions which greatly differ from the crowded intracellular environment. In the following, we describe monitoring both transcription and lac repressor-mediated DNA looping of single DNA molecules in the presence of different concentrations of crowders to bridge the gap between in vitro and in vivo experimentation. We found that crowding shifts the preferred orientation of DNA strands in the looped complex. Crowding also attenuates the rate of transcript elongation and enhances readthrough at the terminator. Clearly, the activities of proteins involved in gene regulation are modified in surprising ways by crowding.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e16"},"PeriodicalIF":0.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12088913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112048","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

Unleashing virus structural biology: Probing protein and membrane intermediates in the dynamic process of membrane fusion. 释放病毒结构生物学：探索膜融合动态过程中的蛋白质和膜中间体。

QRB Discovery Pub Date : 2025-03-31 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.3

Kelly K Lee

{"title":"Unleashing virus structural biology: Probing protein and membrane intermediates in the dynamic process of membrane fusion.","authors":"Kelly K Lee","doi":"10.1017/qrd.2025.3","DOIUrl":"10.1017/qrd.2025.3","url":null,"abstract":"Viruses are highly dynamic macromolecular assemblies. They undergo large-scale changes in structure and organization at nearly every stage of their infectious cycles from virion assembly to maturation, receptor docking, cell entry, uncoating and genome delivery. Understanding structural transformations and dynamics across the virus infectious cycle is an expansive area for research that that can also provide insight into mechanisms for blocking infection, replication, and transmission. Additionally, the processes viruses carry out serve as excellent model systems for analogous cellular processes, but in more accessible form. Capturing and analyzing these dynamic events poses a major challenge for many structural biological approaches due to the size and complexity of the assemblies and the heterogeneity and transience of the functional states that are populated. Here we examine the process of protein-mediated membrane fusion, which is carried out by specialized machinery on enveloped virus surfaces leading to delivery of the viral genome. Application of two complementary methods, cryo-electron tomography and structural mass spectrometry enable dynamic intermediate states in intact fusion systems to be imaged and probed, providing a new understanding of the mechanisms and machinery that drive this fundamental biological process.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e14"},"PeriodicalIF":0.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12075009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080015","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

An integrated structural and biophysical approach to study carbon metabolism in Mycobacterium tuberculosis. 综合结构和生物物理方法研究结核分枝杆菌的碳代谢。

QRB Discovery Pub Date : 2025-03-12 eCollection Date: 2025-01-01 DOI: 10.1017/qrd.2025.6

Evelyn Y-W Huang, Francis Kuang, Haozhe Wu, Chai Xin Yu, Xiaoxu Chen, Glenda Vasku, Le Thao Anh Nguyen, Katherine J Jeppe, Anna K Coussens, Brooke X C Kwai, Ivanhoe K H Leung

{"title":"An integrated structural and biophysical approach to study carbon metabolism in Mycobacterium tuberculosis.","authors":"Evelyn Y-W Huang, Francis Kuang, Haozhe Wu, Chai Xin Yu, Xiaoxu Chen, Glenda Vasku, Le Thao Anh Nguyen, Katherine J Jeppe, Anna K Coussens, Brooke X C Kwai, Ivanhoe K H Leung","doi":"10.1017/qrd.2025.6","DOIUrl":"10.1017/qrd.2025.6","url":null,"abstract":"Metabolic enzymes are the catalysts that drive the biochemical reactions essential for sustaining life. Many of these enzymes are tightly regulated by feedback mechanisms. To fully understand their roles and modulation, it is crucial to investigate the relationship between their structure, catalytic mechanism, and function. In this perspective, by using three examples from our studies on Mycobacterium tuberculosis (Mtb) isocitrate lyase and related proteins, we highlight how an integrated approach combining structural, activity, and biophysical data provides insights into their biological functions. These examples underscore the importance of employing fast-fail experiments at the early stages of a research project, emphasise the value of complementary techniques in validating findings, and demonstrate how in vitro data combined with chemical, biochemical, and physiological knowledge can lead to a broader understanding of metabolic adaptations in pathogenic bacteria. Finally, we address the unexplored questions in Mtb metabolism and discuss how we expand our approach to include microbiological and bioanalytical techniques to further our understanding. Such an integrated and interdisciplinary strategy has the potential to uncover novel regulatory mechanisms and identify new therapeutic opportunities for the eradication of tuberculosis. The approach can also be broadly applied to investigate other biochemical networks and complex biological systems.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"6 ","pages":"e15"},"PeriodicalIF":0.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12088919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112025","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