QRB Discovery最新文献

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Computer-aided comprehensive explorations of RNA structural polymorphism through complementary simulation methods. 通过互补模拟方法对 RNA 结构多态性进行计算机辅助综合探索。
QRB Discovery Pub Date : 2022-10-17 eCollection Date: 2022-01-01 DOI: 10.1017/qrd.2022.19
Konstantin Röder, Guillaume Stirnemann, Pietro Faccioli, Samuela Pasquali
{"title":"Computer-aided comprehensive explorations of RNA structural polymorphism through complementary simulation methods.","authors":"Konstantin Röder, Guillaume Stirnemann, Pietro Faccioli, Samuela Pasquali","doi":"10.1017/qrd.2022.19","DOIUrl":"10.1017/qrd.2022.19","url":null,"abstract":"<p><p>While RNA folding was originally seen as a simple problem to solve, it has been shown that the promiscuous interactions of the nucleobases result in structural polymorphism, with several competing structures generally observed for non-coding RNA. This inherent complexity limits our understanding of these molecules from experiments alone, and computational methods are commonly used to study RNA. Here, we discuss three advanced sampling schemes, namely Hamiltonian-replica exchange molecular dynamics (MD), ratchet-and-pawl MD and discrete path sampling, as well as the HiRE-RNA coarse-graining scheme, and highlight how these approaches are complementary with reference to recent case studies. While all computational methods have their shortcomings, the plurality of simulation methods leads to a better understanding of experimental findings and can inform and guide experimental work on RNA polymorphism.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e21"},"PeriodicalIF":0.0,"publicationDate":"2022-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980665","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
Towards design of drugs and delivery systems with the Martini coarse-grained model. 利用马蒂尼粗粒度模型设计药物和输送系统。
QRB Discovery Pub Date : 2022-10-12 eCollection Date: 2022-01-01 DOI: 10.1017/qrd.2022.16
Lisbeth R Kjølbye, Gilberto P Pereira, Alessio Bartocci, Martina Pannuzzo, Simone Albani, Alessandro Marchetto, Brian Jiménez-García, Juliette Martin, Giulia Rossetti, Marco Cecchini, Sangwook Wu, Luca Monticelli, Paulo C T Souza
{"title":"Towards design of drugs and delivery systems with the Martini coarse-grained model.","authors":"Lisbeth R Kjølbye, Gilberto P Pereira, Alessio Bartocci, Martina Pannuzzo, Simone Albani, Alessandro Marchetto, Brian Jiménez-García, Juliette Martin, Giulia Rossetti, Marco Cecchini, Sangwook Wu, Luca Monticelli, Paulo C T Souza","doi":"10.1017/qrd.2022.16","DOIUrl":"10.1017/qrd.2022.16","url":null,"abstract":"<p><p>Coarse-grained (CG) modelling with the Martini force field has come of age. By combining a variety of bead types and sizes with a new mapping approach, the newest version of the model is able to accurately simulate large biomolecular complexes at millisecond timescales. In this perspective, we discuss possible applications of the Martini 3 model in drug discovery and development pipelines and highlight areas for future development. Owing to its high simulation efficiency and extended chemical space, Martini 3 has great potential in the area of drug design and delivery. However, several aspects of the model should be improved before Martini 3 CG simulations can be routinely employed in academic and industrial settings. These include the development of automatic parameterisation protocols for a variety of molecule types, the improvement of backmapping procedures, the description of protein flexibility and the development of methodologies enabling efficient sampling. We illustrate our view with examples on key areas where Martini could give important contributions such as drugs targeting membrane proteins, cryptic pockets and protein-protein interactions and the development of soft drug delivery systems.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e19"},"PeriodicalIF":0.0,"publicationDate":"2022-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10301374","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
Applications of machine learning in computer-aided drug discovery. 机器学习在计算机辅助药物研发中的应用。
QRB Discovery Pub Date : 2022-09-01 eCollection Date: 2022-01-01 DOI: 10.1017/qrd.2022.12
Sm Bargeen Alam Turzo, Eric R Hantz, Steffen Lindert
{"title":"Applications of machine learning in computer-aided drug discovery.","authors":"Sm Bargeen Alam Turzo, Eric R Hantz, Steffen Lindert","doi":"10.1017/qrd.2022.12","DOIUrl":"10.1017/qrd.2022.12","url":null,"abstract":"<p><p>Machine learning (ML) has revolutionised the field of structure-based drug design (SBDD) in recent years. During the training stage, ML techniques typically analyse large amounts of experimentally determined data to create predictive models in order to inform the drug discovery process. Deep learning (DL) is a subfield of ML, that relies on multiple layers of a neural network to extract significantly more complex patterns from experimental data, and has recently become a popular choice in SBDD. This review provides a thorough summary of the recent DL trends in SBDD with a particular focus on de novo drug design, binding site prediction, and binding affinity prediction of small molecules.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e14"},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/aa/4e/S2633289222000126a.PMC10392679.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283209","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
Integrative structural modelling and visualisation of a cellular organelle. 细胞器的综合结构建模和可视化。
QRB Discovery Pub Date : 2022-08-09 eCollection Date: 2022-01-01 DOI: 10.1017/qrd.2022.10
Ludovic Autin, Brett A Barbaro, Andrew I Jewett, Axel Ekman, Shruti Verma, Arthur J Olson, David S Goodsell
{"title":"Integrative structural modelling and visualisation of a cellular organelle.","authors":"Ludovic Autin, Brett A Barbaro, Andrew I Jewett, Axel Ekman, Shruti Verma, Arthur J Olson, David S Goodsell","doi":"10.1017/qrd.2022.10","DOIUrl":"10.1017/qrd.2022.10","url":null,"abstract":"<p><p>Models of insulin secretory vesicles from pancreatic beta cells have been created using the cellPACK suite of tools to research, curate, construct and visualise the current state of knowledge. The model integrates experimental information from proteomics, structural biology, cryoelectron microscopy and X-ray tomography, and is used to generate models of mature and immature vesicles. A new method was developed to generate a confidence score that reconciles inconsistencies between three available proteomes using expert annotations of cellular localisation. The models are used to simulate soft X-ray tomograms, allowing quantification of features that are observed in experimental tomograms, and in turn, allowing interpretation of X-ray tomograms at the molecular level.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e11"},"PeriodicalIF":0.0,"publicationDate":"2022-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9953783","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
Erratum: Comparing 2 crystal structures and 12 AlphaFold2-predicted human membrane glucose transporters and their water-soluble glutamine, threonine and tyrosine variants - CORRIGENDUM. 勘误:比较 2 个晶体结构和 12 个 AlphaFold2 预测的人类膜葡萄糖转运体及其水溶性谷氨酰胺、苏氨酸和酪氨酸变体 - CORRIGENDUM。
QRB Discovery Pub Date : 2022-07-21 eCollection Date: 2022-01-01 DOI: 10.1017/qrd.2022.8
Eva Smorodina, Fei Tao, Rui Qing, David Jin, Steve Yang, Shuguang Zhang
{"title":"Erratum: Comparing 2 crystal structures and 12 AlphaFold2-predicted human membrane glucose transporters and their water-soluble glutamine, threonine and tyrosine variants - CORRIGENDUM.","authors":"Eva Smorodina, Fei Tao, Rui Qing, David Jin, Steve Yang, Shuguang Zhang","doi":"10.1017/qrd.2022.8","DOIUrl":"10.1017/qrd.2022.8","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1017/qrd.2022.6.].</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e8"},"PeriodicalIF":0.0,"publicationDate":"2022-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9921041","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
Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps. 针对实验和混合低温电镜密度图的AlphaFold2模型的改进。
QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.13
Maytha Alshammari, Willy Wriggers, Jiangwen Sun, Jing He
{"title":"Refinement of AlphaFold2 models against experimental and hybrid cryo-EM density maps.","authors":"Maytha Alshammari,&nbsp;Willy Wriggers,&nbsp;Jiangwen Sun,&nbsp;Jing He","doi":"10.1017/qrd.2022.13","DOIUrl":"https://doi.org/10.1017/qrd.2022.13","url":null,"abstract":"<p><p>Recent breakthroughs in deep learning-based protein structure prediction show that it is possible to obtain highly accurate models for a wide range of difficult protein targets for which only the amino acid sequence is known. The availability of accurately predicted models from sequences can potentially revolutionise many modelling approaches in structural biology, including the interpretation of cryo-EM density maps. Although atomic structures can be readily solved from cryo-EM maps of better than 4 Å resolution, it is still challenging to determine accurate models from lower-resolution density maps. Here, we report on the benefits of models predicted by AlphaFold2 (the best-performing structure prediction method at CASP14) on cryo-EM refinement using the Phenix refinement suite for AlphaFold2 models. To study the robustness of model refinement at a lower resolution of interest, we introduced hybrid maps (i.e. experimental cryo-EM maps) filtered to lower resolutions by real-space convolution. The AlphaFold2 models were refined to attain good accuracies above 0.8 TM scores for 9 of the 13 cryo-EM maps. TM scores improved for AlphaFold2 models refined against all 13 cryo-EM maps of better than 4.5 Å resolution, 8 hybrid maps of 6 Å resolution, and 3 hybrid maps of 8 Å resolution. The results show that it is possible (at least with the Phenix protocol) to extend the refinement success below 4.5 Å resolution. We even found isolated cases in which resolution lowering was slightly beneficial for refinement, suggesting that high-resolution cryo-EM maps might sometimes trap AlphaFold2 models in local optima.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/49/a8/S2633289222000138a.PMC10361706.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9905304","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: 3
Inconsistent treatments of the kinetics of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) impair assessment of its diagnostic potential. 聚类规则间隔短回文重复序列(CRISPR)动力学的不一致处理损害了其诊断潜力的评估。
QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.7
Juan G Santiago
{"title":"Inconsistent treatments of the kinetics of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) impair assessment of its diagnostic potential.","authors":"Juan G Santiago","doi":"10.1017/qrd.2022.7","DOIUrl":"https://doi.org/10.1017/qrd.2022.7","url":null,"abstract":"<p><p>The scientific and technological advent of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is one of the most exciting developments of the past decade, particularly in the field of gene editing. The technology has two essential components, (1) a guide RNA to match a targeted gene and (2) a CRISPR-associated protein (e.g. Cas 9, Cas12 or Cas13) that acts as an endonuclease to specifically cut DNA. This specificity and reconfigurable nature of CRISPR has also spurred intense academic and commercial interest in the development of CRISPR-based molecular diagnostics. CRISPR Cas12 and Cas13 orthologs are most commonly applied to diagnostics, and these cleave and become activated by DNA and RNA targets, respectively. Despite the intense research interest, the limits of detection (LoDs) and applications of CRISP-based diagnostics remain an open question. A major reason for this is that reports of kinetic rates have been widely inconsistent, and the vast majority of these reports contain gross errors including violations of basic conservation and kinetic rate laws. It is the intent of this <i>Perspective</i> to bring attention to these issues and to identify potential improvements in the manner in which CRISPR kinetic rates and assay LoDs are reported and compared. The CRISPR field would benefit from verifications of self-consistency of data, providing sufficient data for reproduction of experiments, and, in the case of reports of novel assay LoDs, concurrent reporting of the associated kinetic rate constants. The early development of CRISPR-based diagnostics calls for self-reflection and urges us to proceed with caution.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e9"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283211","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
Challenges and frontiers of computational modelling of biomolecular recognition. 生物分子识别计算建模的挑战与前沿。
QRB Discovery Pub Date : 2022-01-01 Epub Date: 2022-08-19 DOI: 10.1017/qrd.2022.11
Jinan Wang, Apurba Bhattarai, Hung Nguyen Do, Yinglong Miao
{"title":"Challenges and frontiers of computational modelling of biomolecular recognition.","authors":"Jinan Wang, Apurba Bhattarai, Hung Nguyen Do, Yinglong Miao","doi":"10.1017/qrd.2022.11","DOIUrl":"10.1017/qrd.2022.11","url":null,"abstract":"<p><p>Biomolecular recognition including binding of small molecules, peptides and proteins to their target receptors plays a key role in cellular function and has been targeted for therapeutic drug design. However, the high flexibility of biomolecules and slow binding and dissociation processes have presented challenges for computational modeling. Here, we review the challenges and computational approaches developed to characterize biomolecular binding, including molecular docking, Molecular Dynamics (MD) simulations (especially enhanced sampling) and Machine Learning. Further improvements are still needed in order to accurately and efficiently characterize binding structures, mechanisms, thermodynamics and kinetics of biomolecules in the future.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9729755","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 conformational plasticity of the selectivity filter methionines controls the in-cell Cu(I) uptake through the CTR1 transporter. 选择性过滤蛋氨酸的构象可塑性通过CTR1转运体控制细胞内Cu(I)的摄取。
QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.2
Pavel Janoš, Jana Aupič, Sharon Ruthstein, Alessandra Magistrato
{"title":"The conformational plasticity of the selectivity filter methionines controls the in-cell Cu(I) uptake through the CTR1 transporter.","authors":"Pavel Janoš,&nbsp;Jana Aupič,&nbsp;Sharon Ruthstein,&nbsp;Alessandra Magistrato","doi":"10.1017/qrd.2022.2","DOIUrl":"https://doi.org/10.1017/qrd.2022.2","url":null,"abstract":"<p><p>Copper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity copper transporter 1 (CTR1), being the main in-cell copper [Cu(I)] entry route, tightly regulates its cellular uptake via a still elusive mechanism. Here, all-atoms simulations unlock the molecular terms of Cu(I) transport in eukaryotes disclosing that the two methionine (Met) triads, forming the selectivity filter, play an unprecedented dual role both enabling selective Cu(I) transport and regulating its uptake rate thanks to an intimate coupling between the conformational plasticity of their bulky side chains and the number of bound Cu(I) ions. Namely, the Met residues act as a gate reducing the Cu(I) import rate when two ions simultaneously bind to CTR1. This may represent an elegant autoregulatory mechanism through which CTR1 protects the cells from excessively high, and hence toxic, in-cell Cu(I) levels. Overall, our outcomes resolve fundamental questions in CTR1 biology and open new windows of opportunity to tackle diseases associated with an imbalanced copper uptake.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e3"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10649800","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
On the osmotic pressure of cells. 细胞的渗透压。
QRB Discovery Pub Date : 2022-01-01 DOI: 10.1017/qrd.2022.3
Håkan Wennerström, Mikael Oliveberg
{"title":"On the osmotic pressure of cells.","authors":"Håkan Wennerström,&nbsp;Mikael Oliveberg","doi":"10.1017/qrd.2022.3","DOIUrl":"https://doi.org/10.1017/qrd.2022.3","url":null,"abstract":"<p><p>The chemical potential of water () provides an essential thermodynamic characterization of the environment of living organisms, and it is of equal significance as the temperature. For cells, is conventionally expressed in terms of the osmotic pressure (π<sub>osm</sub>). We have previously suggested that the main contribution to the intracellular π<sub>osm</sub> of the bacterium <i>E. coli</i> is from soluble negatively-charged proteins and their counter-ions. Here, we expand on this analysis by examining how evolutionary divergent cell types cope with the challenge of maintaining π<sub>osm</sub> within viable values. Complex organisms, like mammals, maintain constant internal π<sub>osm</sub> ≈ 0.285 osmol, matching that of 0.154 M NaCl. For bacteria it appears that optimal growth conditions are found for similar or slightly higher π<sub>osm</sub> (0.25-0.4 osmol), despite that they represent a much earlier stage in evolution. We argue that this value reflects a general adaptation for optimising metabolic function under crowded intracellular conditions. Environmental π<sub>osm</sub> that differ from this optimum require therefore special measures, as exemplified with gram-positive and gram-negative bacteria. To handle such situations, their membrane encapsulations allow for a compensating turgor pressure that can take both positive and negative values, where positive pressures allow increased frequency of metabolic events through increased intracellular protein concentrations. A remarkable exception to the rule of 0.25-0.4 osmol, is found for halophilic archaea with internal π<sub>osm</sub> ≈ 15 osmol. The internal organization of these archaea differs in that they utilize a repulsive electrostatic mechanism operating only in the ionic-liquid regime to avoid aggregation, and that they stand out from other organisms by having no turgor pressure.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e12"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10301376","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: 5
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