QRB Discovery最新文献_第2页

“Druggability” of the PAS domains of human PASK kinase, a therapeutic target for metabolic and liver disorders 人类 PASK 激酶 PAS 结构域的 "可药性"--新陈代谢和肝脏疾病的治疗靶标

QRB Discovery Pub Date : 2024-02-02 DOI: 10.1017/qrd.2024.1

Shangze Xu, Lanyu Fan, Piotr Zaborniak, Ruidi Zhu, Haoyuan Ji, Katrina S Madden, J. V. de Souza, Agnieszka K. Bronowska

引用次数: 0

Protein structures unravel the signatures and patterns of deep time evolution 蛋白质结构揭示了深层进化的特征和模式

QRB Discovery Pub Date : 2024-01-29 DOI: 10.1017/qrd.2024.4

Ajith Harish

引用次数: 0

Sequence – Dynamics – Function Relationships in Protein Tyrosine Phosphatases 蛋白酪氨酸磷酸酶的序列-动力学-功能关系

QRB Discovery Pub Date : 2024-01-24 DOI: 10.1017/qrd.2024.3

Rory M. Crean, Marina Corbella, A. R. Calixto, A. Hengge, S. C. Kamerlin

{"title":"Sequence – Dynamics – Function Relationships in Protein Tyrosine Phosphatases","authors":"Rory M. Crean, Marina Corbella, A. R. Calixto, A. Hengge, S. C. Kamerlin","doi":"10.1017/qrd.2024.3","DOIUrl":"https://doi.org/10.1017/qrd.2024.3","url":null,"abstract":"Protein tyrosine phosphatases are crucial regulators of cellular signaling. Their activity is regulated by the motion of a conserved loop, the WPD-loop, from a catalytically inactive open to a catalytically active closed conformation. WPD-loop motion optimally positions a catalytically critical residue into the active site, and is directly linked to the turnover number of these enzymes. Crystal structures of chimeric PTPs constructed by grafting parts of the WPD-loop sequence of PTP1B onto the scaffold of YopH showed WPD-loops in a wide-open conformation never previously observed in either parent enzyme. This wide-open conformation has, however, been observed upon binding of small molecule inhibitors to other PTPs, suggesting the potential of targeting it for drug discovery efforts. Here, we have performed simulations of both enzymes and show that there are negligible energetic differences in the chemical step of catalysis, but significant differences in the dynamical properties of the WPD-loop. Detailed interaction network analysis provides insight into the molecular basis for this population shift to a wide-open conformation. Taken together, our study provides insight into the links between loop dynamics and chemistry in these YopH variants specifically, and how WPD-loop dynamic can be engineered through modification of the internal protein interaction network.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"27 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139599982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural bioinformatics studies of six human ABC transporters and their AlphaFold2-predicted water-soluble QTY variants 六种人类 ABC 转运体及其 AlphaFold2 预测水溶性 QTY 变体的结构生物信息学研究

QRB Discovery Pub Date : 2024-01-19 DOI: 10.1017/qrd.2024.2

Emily Pan, Fei Tao, Eva Smorodina, Shuguang Zhang

引用次数: 0

How sequence alterations enhance the stability and delay expansion of DNA triplet repeat domains. 序列改变如何增强DNA三联体重复结构域的稳定性和延迟扩展。

QRB Discovery Pub Date : 2023-11-06 eCollection Date: 2023-01-01 DOI: 10.1017/qrd.2023.6

Jens Völker, Kenneth J Breslauer

{"title":"How sequence alterations enhance the stability and delay expansion of DNA triplet repeat domains.","authors":"Jens Völker, Kenneth J Breslauer","doi":"10.1017/qrd.2023.6","DOIUrl":"10.1017/qrd.2023.6","url":null,"abstract":"DNA sequence alterations within DNA repeat domains inexplicably enhance the stability and delay the expansion of interrupted repeat domains. Here we propose mechanisms that rationalise such unanticipated outcomes. Specifically, we describe how interruption of a DNA repeat domain restricts the ensemble space available to dynamic, slip out, repeat bulge loops by introducing energetic barriers to loop migration. We explain how such barriers arise because some possible loop isomers result in energetically costly mismatches in the duplex portion of the repeat domain. We propose that the reduced ensemble space is the causative feature for the observed delay in repeat DNA expansion. We further posit that the observed loss of the interrupting repeat in some expanded DNAs reflects the transient occupation of loop isomer positions that result in a mismatch in the duplex stem due to 'leakiness' in the energy barrier. We propose that if the lifetime of such a low probability event allows for recognition by the mismatch repair system, then 'repair' of the repeat interruption can occur; thereby rationalising the absence of the interruption in the final expanded DNA 'product.' Our proposed mechanistic pathways provide reasoned explanations for what have been described as 'puzzling' observations, while also yielding insights into a biomedically important set of coupled genotypic phenomena that map the linkage between DNA origami thermodynamics and phenotypic disease states.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"4 ","pages":"e8"},"PeriodicalIF":0.0,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10641665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107592401","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

Energy landscapes and heat capacity signatures for peptides correlate with phase separation propensity. 肽的能量景观和热容特征与相分离倾向相关。

QRB Discovery Pub Date : 2023-09-05 eCollection Date: 2023-01-01 DOI: 10.1017/qrd.2023.5

Nicy, Rosana Collepardo-Guevara, Jerelle A Joseph, David J Wales

{"title":"Energy landscapes and heat capacity signatures for peptides correlate with phase separation propensity.","authors":"Nicy, Rosana Collepardo-Guevara, Jerelle A Joseph, David J Wales","doi":"10.1017/qrd.2023.5","DOIUrl":"https://doi.org/10.1017/qrd.2023.5","url":null,"abstract":"Phase separation plays an important role in the formation of membraneless compartments within the cell and intrinsically disordered proteins with low-complexity sequences can drive this compartmentalisation. Various intermolecular forces, such as aromatic-aromatic and cation-aromatic interactions, promote phase separation. However, little is known about how the ability of proteins to phase separate under physiological conditions is encoded in their energy landscapes and this is the focus of the present investigation. Our results provide a first glimpse into how the energy landscapes of minimal peptides that contain - and cation- interactions differ from the peptides that lack amino acids with such interactions. The peaks in the heat capacity () as a function of temperature report on alternative low-lying conformations that differ significantly in terms of their enthalpic and entropic contributions. The analysis and subsequent quantification of frustration of the energy landscape suggest that the interactions that promote phase separation lead to features (peaks or inflection points) at low temperatures in . More features may occur for peptides containing residues with better phase separation propensity and the energy landscape is more frustrated for such peptides. Overall, this work links the features in the underlying single-molecule potential energy landscapes to their collective phase separation behaviour and identifies quantities ( and frustration metric) that can be utilised in soft material design.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"4 ","pages":"e7"},"PeriodicalIF":0.0,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10523320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41118391","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: 1

On the micelle formation of DNAJB6b. 关于 DNAJB6b 的胶束形成。

QRB Discovery Pub Date : 2023-08-15 eCollection Date: 2023-01-01 DOI: 10.1017/qrd.2023.4

Andreas Carlsson, Ulf Olsson, Sara Linse

{"title":"On the micelle formation of DNAJB6b.","authors":"Andreas Carlsson, Ulf Olsson, Sara Linse","doi":"10.1017/qrd.2023.4","DOIUrl":"10.1017/qrd.2023.4","url":null,"abstract":"The human chaperone DNAJB6b increases the solubility of proteins involved in protein aggregation diseases and suppresses the nucleation of amyloid structures. Due to such favourable properties, DNAJB6b has gained increasing attention over the past decade. The understanding of how DNAJB6b operates on a molecular level may aid the design of inhibitors against amyloid formation. In this work, fundamental aspects of DNAJB6b self-assembly have been examined, providing a basis for future experimental designs and conclusions. The results imply the formation of large chaperone clusters in a concentration-dependent manner. Microfluidic diffusional sizing (MDS) was used to evaluate how DNAJB6b average hydrodynamic radius varies with concentration. We found that, in 20 mM sodium phosphate buffer, 0.2 mM EDTA, at pH 8.0 and room temperature, DNAJB6b displays a micellar behaviour, with a critical micelle concentration (CMC) of around 120 nM. The average hydrodynamic radius appears to be concentration independent between ∼10 μM and 100 μM, with a mean radius of about 12 nm. The CMC found by MDS is supported by native agarose gel electrophoresis and the size distribution appears bimodal in the DNAJB6b concentration range ∼100 nM to 4 μM.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"4 ","pages":"e6"},"PeriodicalIF":0.0,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10049952","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

Chasing collective variables using temporal data-driven strategies. 利用时间数据驱动策略追逐集体变量。

QRB Discovery Pub Date : 2023-01-06 eCollection Date: 2023-01-01 DOI: 10.1017/qrd.2022.23

Haochuan Chen, Christophe Chipot

{"title":"Chasing collective variables using temporal data-driven strategies.","authors":"Haochuan Chen, Christophe Chipot","doi":"10.1017/qrd.2022.23","DOIUrl":"10.1017/qrd.2022.23","url":null,"abstract":"The convergence of free-energy calculations based on importance sampling depends heavily on the choice of collective variables (CVs), which in principle, should include the slow degrees of freedom of the biological processes to be investigated. Autoencoders (AEs), as emerging data-driven dimension reduction tools, have been utilised for discovering CVs. AEs, however, are often treated as black boxes, and what AEs actually encode during training, and whether the latent variables from encoders are suitable as CVs for further free-energy calculations remains unknown. In this contribution, we review AEs and their time-series-based variants, including time-lagged AEs (TAEs) and modified TAEs, as well as the closely related model variational approach for Markov processes networks (VAMPnets). We then show through numerical examples that AEs learn the high-variance modes instead of the slow modes. In stark contrast, time series-based models are able to capture the slow modes. Moreover, both modified TAEs with extensions from slow feature analysis and the state-free reversible VAMPnets (SRVs) can yield orthogonal multidimensional CVs. As an illustration, we employ SRVs to discover the CVs of the isomerizations of N-acetyl-N'-methylalanylamide and trialanine by iterative learning with trajectories from biased simulations. Last, through numerical experiments with anisotropic diffusion, we investigate the potential relationship of time-series-based models and committor probabilities.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"4 ","pages":"e2"},"PeriodicalIF":0.0,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9976165","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

Computational prediction of ω-transaminase selectivity by deep learning analysis of molecular dynamics trajectories. 基于分子动力学轨迹深度学习分析的ω-转氨酶选择性计算预测。

QRB Discovery Pub Date : 2023-01-01 DOI: 10.1017/qrd.2022.22

Carlos Ramírez-Palacios, Siewert J Marrink

{"title":"Computational prediction of ω-transaminase selectivity by deep learning analysis of molecular dynamics trajectories.","authors":"Carlos Ramírez-Palacios, Siewert J Marrink","doi":"10.1017/qrd.2022.22","DOIUrl":"https://doi.org/10.1017/qrd.2022.22","url":null,"abstract":"We previously presented a computational protocol to predict the enzymatic (enantio)selectivity of an ω-transaminase towards a set of ligands (Ramírez-Palacios et al. (2021) Journal of Chemical Information and Modeling 61(11), 5569-5580) by counting the number of binding poses present in molecular dynamics (MD) simulations that met a defined set of geometric criteria. The geometric criteria consisted of a hand-crafted set of distances, angles and dihedrals deemed to be important for the enzymatic reaction to take place. In this work, the MD trajectories are reanalysed using a deep-learning approach to predict the enantiopreference of the enzyme without the need for hand-crafted criteria. We show that a convolutional neural network is capable of classifying the trajectories as belonging to the 'reactive' or 'non-reactive' enantiomer (binary classification) with a good accuracy (>0.90). The new method reduces the computational cost of the methodology, because it does not necessitate the sampling approach from the previous work. We also show that analysing how neural networks reach specific decisions can aid hand-crafted approaches (e.g. definition of near-attack conformations, or binding poses).","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"4 ","pages":"e1"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9925965","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: 1

Sulfur-mediated chalcogen versus hydrogen bonds in proteins: a see-saw effect in the conformational space. 蛋白质中硫介导的硫与氢键:构象空间中的跷跷板效应。

QRB Discovery Pub Date : 2023-01-01 DOI: 10.1017/qrd.2023.3

Vishal Annasaheb Adhav, Sanket Satish Shelke, Pananghat Balanarayan, Kayarat Saikrishnan

{"title":"Sulfur-mediated chalcogen versus hydrogen bonds in proteins: a see-saw effect in the conformational space.","authors":"Vishal Annasaheb Adhav, Sanket Satish Shelke, Pananghat Balanarayan, Kayarat Saikrishnan","doi":"10.1017/qrd.2023.3","DOIUrl":"https://doi.org/10.1017/qrd.2023.3","url":null,"abstract":"Divalent sulfur (S) forms a chalcogen bond (Ch-bond) via its σ-holes and a hydrogen bond (H-bond) via its lone pairs. The relevance of these interactions and their interplay for protein structure and function is unclear. Based on the analyses of the crystal structures of small organic/organometallic molecules and proteins and their molecular electrostatic surface potential, we show that the reciprocity of the substituent-dependent strength of the σ-holes and lone pairs correlates with the formation of either Ch-bond or H-bond. In proteins, cystines preferentially form Ch-bonds, metal-chelated cysteines form H-bonds, while methionines form either of them with comparable frequencies. This has implications for the positioning of these residues and their role in protein structure and function. Computational analyses reveal that the S-mediated interactions stabilise protein secondary structures by mechanisms such as helix capping and protecting free β-sheet edges by negative design. The study highlights the importance of S-mediated Ch-bond and H-bond for understanding protein folding and function, the development of improved strategies for protein/peptide structure prediction and design and structure-based drug discovery.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"4 ","pages":"e5"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9976166","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: 2