QRB Discovery最新文献

{"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}

{"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_osm). We have previously suggested that the main contribution to the intracellular π_osm 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_osm within viable values. Complex organisms, like mammals, maintain constant internal π_osm ≈ 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_osm (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_osm 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_osm ≈ 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}

{"title":"Reconstituted virus-nucleus system reveals mechanics of herpesvirus genome uncoating.","authors":"Alex Evilevitch,&nbsp;Efthymios Tsimtsirakis","doi":"10.1017/qrd.2021.14","DOIUrl":"https://doi.org/10.1017/qrd.2021.14","url":null,"abstract":"<p><p>The viral replication cycle is controlled by information transduced through both molecular and mechanical interactions. Viral infection mechanics remains largely unexplored, however, due to the complexity of cellular mechanical responses over the course of infection as well as a limited ability to isolate and probe these responses. Here, we develop an experimental system consisting of herpes simplex virus type 1 (HSV-1) capsids bound to isolated and reconstituted cell nuclei, which allows direct probing of capsid-nucleus mechanics with atomic force microscopy (AFM). Major mechanical transformations occur in the host nucleus when pressurised viral DNA ejects from HSV-1 capsids docked at the nuclear pore complexes (NPCs) on the nuclear membrane. This leads to structural rearrangement of the host chromosome, affecting its compaction. This in turn regulates viral genome replication and transcription dynamics as well as the decision between a lytic or latent course of infection. AFM probing of our reconstituted capsid-nucleus system provides high-resolution topographical imaging of viral capsid docking at the NPCs as well as force volume mapping of the infected nucleus surface, reflecting mechanical transformations associated with chromatin compaction and stiffness of nuclear lamina (to which chromatin is tethered). This experimental system provides a novel platform for investigation of virus-host interaction mechanics during viral genome penetration into the nucleus.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e2"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283210","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}

{"title":"<i>α</i>-Synuclein-induced deformation of small unilamellar vesicles.","authors":"Katarzyna Makasewicz,&nbsp;Stefan Wennmalm,&nbsp;Sara Linse,&nbsp;Emma Sparr","doi":"10.1017/qrd.2022.9","DOIUrl":"https://doi.org/10.1017/qrd.2022.9","url":null,"abstract":"<p><p><i>α</i>-Synuclein is a small neuronal protein that reversibly associates with lipid membranes. The membrane interactions are believed to be central to the healthy function of this protein involved in synaptic plasticity and neurotransmitter release. <i>α</i>-Synuclein has been speculated to induce vesicle fusion as well as fission, processes which are analogous to each other but proceed in different directions and involve different driving forces. In the current work, we analyse <i>α</i>-synuclein-induced small unilamellar vesicle deformation from a thermodynamics point of view. We show that the structures interpreted in the literature as fusion intermediates are in fact a stable deformed state and neither fusion nor vesicle clustering occurs. We speculate on the driving force for the observed deformation and put forward a hypothesis that <i>α</i>-synuclein self-assembly on the lipid membrane precedes and induces membrane remodelling.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e10"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10301370","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}

{"title":"Performance evaluation of flexible macrocycle docking in AutoDock.","authors":"Matthew Holcomb,&nbsp;Diogo Santos-Martins,&nbsp;Andreas F Tillack,&nbsp;Stefano Forli","doi":"10.1017/qrd.2022.18","DOIUrl":"https://doi.org/10.1017/qrd.2022.18","url":null,"abstract":"Abstract Abstract Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands flexibly, without requiring the enumeration of macrocyclic conformers before docking. Here, we characterize the performance of the method for handling macrocyclic compounds, which is implemented and the default behaviour for ligand preparation with our ligand preparation pipeline, Meeko. A pseudoatom is used to encode bond geometry and produce an anisotropic closure force for macrocyclic rings. This method is evaluated on a diverse set of small molecule and peptide macrocycles, ranging from 7- to 33-membered rings, showing little accuracy loss compared to rigid redocking of the X-ray macrocycle conformers. This suggests that for conformationally flexible macrocycles with unknown binding modes, this method can be effectively used to predict the macrocycle conformation.","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e18"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9926278","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}

{"title":"Homologous basic helix-loop-helix transcription factors induce distinct deformations of torsionally-stressed DNA: a potential transcription regulation mechanism.","authors":"Johanna Hörberg,&nbsp;Kevin Moreau,&nbsp;Anna Reymer","doi":"10.1017/qrd.2022.5","DOIUrl":"https://doi.org/10.1017/qrd.2022.5","url":null,"abstract":"<p><p>Changing torsional restraints on DNA is essential for the regulation of transcription. Torsional stress, introduced by RNA polymerase, can propagate along chromatin facilitating topological transitions and modulating the specific binding of transcription factors (TFs) to DNA. Despite the importance, the mechanistic details on how torsional stress impacts the TFs-DNA complexation remain scarce. Herein, we address the impact of torsional stress on DNA complexation with homologous human basic helix-loop-helix (BHLH) hetero- and homodimers: MycMax, MadMax and MaxMax. The three TF dimers exhibit specificity towards the same DNA consensus sequence, the <i>E</i>-box response element, while regulating different transcriptional pathways. Using microseconds-long atomistic molecular dynamics simulations together with the torsional restraint that controls DNA total helical twist, we gradually over- and underwind naked and complexed DNA to a maximum of ± 5°/bp step. We observe that the binding of the BHLH dimers results in a similar increase in DNA torsional rigidity. However, under torsional stress the BHLH dimers induce distinct DNA deformations, characterised by changes in DNA grooves geometry and a significant asymmetric DNA bending. Supported by bioinformatics analyses, our data suggest that torsional stress may contribute to the execution of differential transcriptional programs of the homologous TFs by modulating their collaborative interactions.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e4"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10301375","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}

{"title":"Modelling peptide-protein complexes: docking, simulations and machine learning.","authors":"Arup Mondal,&nbsp;Liwei Chang,&nbsp;Alberto Perez","doi":"10.1017/qrd.2022.14","DOIUrl":"https://doi.org/10.1017/qrd.2022.14","url":null,"abstract":"<p><p>Peptides mediate up to 40% of protein interactions, their high specificity and ability to bind in places where small molecules cannot make them potential drug candidates. However, predicting peptide-protein complexes remains more challenging than protein-protein or protein-small molecule interactions, in part due to the high flexibility peptides have. In this review, we look at the advances in docking, molecular simulations and machine learning to tackle problems related to peptides such as predicting structures, binding affinities or even kinetics. We specifically focus on explaining the number of docking programmes and force fields used in molecular simulations, so a prospective user can have an educated guess as to why choose one modelling tool or another to address their scientific questions.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e17"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980664","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}

{"title":"Graph deep learning locates magnesium ions in RNA.","authors":"Yuanzhe Zhou,&nbsp;Shi-Jie Chen","doi":"10.1017/qrd.2022.17","DOIUrl":"https://doi.org/10.1017/qrd.2022.17","url":null,"abstract":"<p><p>Magnesium ions (Mg²⁺) are vital for RNA structure and cellular functions. Present efforts in RNA structure determination and understanding of RNA functions are hampered by the inability to accurately locate Mg²⁺ ions in an RNA. Here we present a machine-learning method, originally developed for computer visual recognition, to predict Mg²⁺ binding sites in RNA molecules. By incorporating geometrical and electrostatic features of RNA, we capture the key ingredients of Mg²⁺-RNA interactions, and from deep learning, predict the Mg²⁺ density distribution. Five-fold cross-validation on a dataset of 177 selected Mg²⁺-containing structures and comparisons with different methods validate the approach. This new approach predicts Mg²⁺ binding sites with notably higher accuracy and efficiency. More importantly, saliency analysis for eight different Mg²⁺ binding motifs indicates that the model can reveal critical coordinating atoms for Mg²⁺ ions and ion-RNA inner/outer-sphere coordination. Furthermore, implementation of the model uncovers new Mg²⁺ binding motifs. This new approach may be combined with X-ray crystallography structure determination to pinpoint the metal ion binding sites.</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/PMC10249658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9622248","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}

{"title":"Pulmonary surfactant and COVID-19: A new synthesis.","authors":"Barry Ninham,&nbsp;Brandon Reines,&nbsp;Matthew Battye,&nbsp;Paul Thomas","doi":"10.1017/qrd.2022.1","DOIUrl":"https://doi.org/10.1017/qrd.2022.1","url":null,"abstract":"<p><strong>Chapter 1: </strong>COVID-19 pathogenesis poses paradoxes difficult to explain with traditional physiology. For instance, since type II pneumocytes are considered the primary cellular target of SARS-CoV-2; as these produce pulmonary surfactant (PS), the possibility that insufficient PS plays a role in COVID-19 pathogenesis has been raised. However, the opposite of predicted <i>high</i> alveolar surface tension is found in many <i>early</i> COVID-19 patients: paradoxically normal lung volumes and high compliance occur, with profound hypoxemia. That 'COVID anomaly' was quickly rationalised by invoking traditional vascular mechanisms-mainly because of surprisingly preserved alveolar surface in early hypoxemic cases. However, that quick rejection of alveolar damage only occurred because the actual mechanism of gas exchange has long been presumed to be non-problematic, due to diffusion through the alveolar surface. On the contrary, we provide physical chemical evidence that <i>gas exchange occurs by an process of expansion and contraction of the three-dimensional structures of PS and its associated proteins.</i> This view explains anomalous observations from the level of cryo-TEM to whole individuals. It encompasses results from premature infants to the deepest diving seals. Once understood, the COVID anomaly dissolves and is straightforwardly explained as covert viral damage to the 3D structure of PS, with direct treatment implications. As a natural experiment, the SARS-CoV-2 virus itself has helped us to simplify and clarify not only the nature of dyspnea and its relationship to pulmonary compliance, but also the fine detail of the PS including such features as water channels which had heretofore been entirely unexpected.</p><p><strong>Chapter 2: </strong>For a long time, physical, colloid and surface chemistry have not intersected with physiology and cell biology as much as we might have hoped. The reasons are starting to become clear. The discipline of physical chemistry suffered from serious unrecognised omissions that rendered it ineffective. These foundational defects included omission of specific ion molecular forces and hydration effects. The discipline lacked a predictive theory of self-assembly of lipids and proteins. Worse, theory omitted any role for dissolved gases, O₂, N₂, CO₂, and their existence as stable nanobubbles above physiological salt concentration. Recent developments have gone some way to explaining the foam-like lung surfactant structures and function. It delivers O₂/N₂ as nanobubbles, and efflux of CO₂, and H₂O nanobubbles at the alveolar surface. Knowledge of pulmonary surfactant structure allows an explanation of the mechanism of corona virus entry, and differences in infectivity of different variants. CO₂ nanobubbles, resulting from metabolism passing through the molecular frit provided by the glycocalyx of venous tissue, f","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e6"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9970176","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}

{"title":"Comparing 2 crystal structures and 12 AlphaFold2-predicted human membrane glucose transporters and their water-soluble glutamine, threonine and tyrosine variants.","authors":"Eva Smorodina,&nbsp;Fei Tao,&nbsp;Rui Qing,&nbsp;David Jin,&nbsp;Steve Yang,&nbsp;Shuguang Zhang","doi":"10.1017/qrd.2022.6","DOIUrl":"https://doi.org/10.1017/qrd.2022.6","url":null,"abstract":"<p><p>Membrane transporters including glucose transporters (GLUTs) are involved in cellular energy supplies, cell metabolism and other vital biological activities. They have also been implicated in cancer proliferation and metastasis, thus they represent an important target in combatting cancer. However, membrane transporters are very difficult to study due to their multispan transmembrane properties. The new computational tool, AlphaFold2, offers highly accurate predictions of three-dimensional protein structures. The glutamine, threonine and tyrosine (QTY) code provides a systematic method of rendering hydrophobic sequences into hydrophilic ones. Here, we present computational studies of native integral membrane GLUTs with 12 transmembrane helical segments determined by X-ray crystallography and CryoEM, comparing the AlphaFold2-predicted native structure to their water-soluble QTY variants predicted by AlphaFold2. In the native structures of the transmembrane helices, there are hydrophobic amino acids leucine (L), isoleucine (I), valine (V) and phenylalanine (F). Applying the QTY code, these hydrophobic amino acids are systematically replaced by hydrophilic amino acids, glutamine (Q), threonine (T) and tyrosine (Y) rendering them water-soluble. We present the superposed structures of native GLUTs and their water-soluble QTY variants. The superposed structures show remarkable similar residue mean square distance values between 0.47 and 3.6 Å (most about 1-2 Å) despite >44% transmembrane amino acid differences. We also show the differences of hydrophobicity patches between the native membrane transporters and their QTY variants. We explain the rationale why the membrane protein QTY variants become water-soluble. Our study provides insight into the differences between the hydrophobic helices and hydrophilic helices, and offers confirmation of the QTY method for studying multispan transmembrane proteins and other aggregated proteins through their water-soluble variants.</p>","PeriodicalId":34636,"journal":{"name":"QRB Discovery","volume":"3 ","pages":"e5"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10392618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9980666","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}