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Dynamically induced water transport through membrane cotransporters
No full textV zadnjem desetletju se je razumevanje molekulskih mehanizmov membranskih prenašalcev dramatično povečalo, predvsem na račun eksperimentalno določenih struktur konformer, ki ustrezajo različnim funkcionalnim stanjem membranskih prenašalcev. Še vedno pa le-teh ni dovolj za natančen opis mehanističnih lastnosti tovrstnih proteinov. Membranski koprenašalni proteini so podvrženi velikim strukturnim preureditvam, ki so na splošno povezane z dogodki vezave in so bistvene za njihovo biološko funkcijo. Z združevanjem strukturnega znanja s kemičnimi, biofizikalnimi in računalniškimi pristopi se je začelo pojavljati jasnejše razumevanje različnih načinov transporta majhnih molekul in sorodnih zvrsti. Računalniški pristop predstavlja v tem primeru pomembno orodje, ki omogoča proučevanje delovanja teh sistemov na molekulskem nivoju in proučevanje sklopitev biofizikalnih lastnosti sistemov z eksperimentalno merljivimi količinami.
Membranski prenašalci se lahko, poleg njihove glavne vloge specifičnih prenašalcev za majhne molekule in ione, obnašajo tudi kot vodni kanali. Vendar pa pogosto v različnih sistemih ni natančno znan niti položaj glavne poti prehoda vode v proteinu niti njihov funkcionalni mehanizem delovanja. Na splošno je celoten proces transporta substratov zagotovljen s prehodi »izmeničnega dostopa« med dvema glavnima konformacijskima stanjema: navzven obrnjena (OF) in navznoter obrnjena (IF) stanja, pri katerih je dostopnost substrata premaknjena z ene strani membrane na drugo.
V okviru naše študije smo se osredotočili na transportne mehanizme vode v človeškem natrij glukoznem koprenašalcu 1 (SGLT1), pri študiju katerega pa je bilo do sedaj prikazanih veliko nasprotujočih hipotez o delovanju, ki po našem mnenju niso bile dovolj podprte z natančno biofizikalno študijo mehanizma. Namen študije je pojasniti vodni transport v omenjenem prenašalcu kot splošen mehanizem, ki bi se ga dalo prenesti tudi na druge membranske prenašalne sisteme, kot tudi na ostale proteinske in neproteinske sisteme. S študijo interne proteinske dinamike z uporabo metod atomistične molekulske dinamike, razvoja metod za zasledovanje difuzijskega in osmotsko pogojenega prehoda vode in specifičnih implementacij analize glavnih komponent (PCA) smo pojasnili mehanizem vodnega transporta v preiskovanem prenašalnem proteinu. Raziskovali smo protein SGLT1, vgrajen v membrano v različnih konformacijskih stanjih, ob prisotnosti ali odsotnosti substratov ter v obliki kompleksov zaviralec-protein. Natančno smo razklopili načine domenskega gibanja transporterja na posamezne komponente, ki dobro opisujejo v literaturi opisan karakterističen način gibanja t.i. "zibajočega snopa" (ang. rocking-bundle), in analizirali vpliv prisotnosti ali odsotnosti ligandov ali zaviralcev na fleksibilnostne lastnosti posameznega načina gibanja, kot tudi celokupnega domenskega gibanja. Ugotovili smo, da ima na prehod vode vpliv domensko gibanje prenašalnega proteina. Ovrednotili smo učinek uporabe zaviralcev na biofizikalne lastnosti proteina in ugotovili, da v primeru vodnega transporta svoj učinek najmočneje izražajo alosterično na mestu, ki ni v neposrednem stiku z vezavnim mestom za sladkorni del vezavnega mesta zaviralca. Predlagamo, da je pri načrtovanju novih zaviralcev smiselno upoštevati tudi kriterij za utrditev strukture oziroma gibanja prenašalca ob vezavi z zaviralcem.
Med simulacijo molekulske dinamike smo zaznali prehod naravnega sladkornega liganda v potencialen nov vezavni žep v SGLT1. Ovrednotili smo biofizikalne lastnosti sistema, v kolikor je sladkorni ligand vezan v osnovnem ali pa v alternativnem vezavnem mestu. Glede na podano možnost vezave liganda v alternativno vezavno mesto smo izvedli virtualno rešetanje knjižnice spojin in z uporabo v tem delu razvitih metod napovedali potencialni učinek izbranega zadetka.In the last decade, the understanding of the molecular mechanisms of membrane transporters has increased dramatically, mainly through experimentally determined conformer structures corresponding to different functional states of membrane transporters. However, these are still insufficient to accurately describe the mechanistic properties of these proteins. Membrane co-transporter proteins undergo major structural rearrangements, generally related to binding events, which are essential for their biological function. By combining structural knowledge with chemical, biophysical and computational approaches, a clearer understanding of the different modes of transport of small molecules and related species is beginning to emerge. In this case, the computational approach represents an important tool that allows the study of the functioning of these systems at the molecular level and the coupling of the biophysical properties of the systems to experimentally measurable quantities.
In addition to their main role as specific carriers for small molecules and ions, membrane carriers can also behave as water channels. However, often in different systems, neither the position of the main water passage pathway in the protein nor their functional mechanism of action is precisely known. In general, the whole process of substrate transport is ensured by "alternating access" transitions between two main conformational states: the outward-facing (OF) and the inward-facing (IF) states, in which the substrate accessibility is shifted from one side of the membrane to the other.
In the context of our study, we focused on the water transport mechanisms in human sodium-glucose co-transporter 1 (SGLT1), the study of which has so far shown numerous conflicting hypotheses of action, which in our opinion have not been sufficiently supported by a detailed biophysical study of the mechanism. The aim of this study is to elucidate the water transport in this transporter as a general mechanism that could be transferred to other membrane transporters as well as to other protein and non-protein systems. By studying the internal protein dynamics using atomistic molecular dynamics methods, the development of methods to trace diffusion- and osmotically-dependent water transport and specific implementations of the principle component analysis (PCA) method, we have elucidated the mechanism of water transport in the carrier protein under investigation. The membrane-embedded SGLT1 protein was investigated in different conformational states, including the states in the presence of ions and substrates, and in the form of inhibitor-protein complexes. We have precisely decomposed the transporter\u27s domain motion modes into individual components that describe the characteristic rocking-bundle motion mode described in the literature and analysed the influence of the presence or absence of ligands or inhibitors on the flexibility properties of each mode as well as of the overall domain motion. We evaluated the effect of the use of inhibitors on the biophysical properties of the protein and found that, in the case of aqueous transport, they express their effect allosterically at a site that is not in direct contact with the binding site for the sugar moiety of the inhibitor binding site. We suggest that the design of new inhibitors should take into account a requirement for the stiffening of protein structure and dynamics upon binding with inhibitor.
Molecular dynamics simulations have detected the transition of the natural sugar ligand to a potential new binding pocket in SGLT1. We have evaluated the biophysical properties of the system insofar as the sugar ligand is bound in either the primary or the alternative binding site. Given an indication of the possibility of ligand binding in the alternative binding site, we performed a virtual search of the compound library and used the developed methods to predict the potential effect of the selected hit
Determination of thermal conductivities in liquids by identifying heat transport in nonequilibrium MD simulations
Get PDFGoing Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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