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Cotranslational protein folding through non-native structural intermediates
No full textCotranslational protein folding follows a distinct pathway shaped by the vectorial emergence of the peptide and spatial constraints of the ribosome exit tunnel. Variations in translation rhythm can cause misfolding linked to disease; however, predicting cotranslational folding pathways remains challenging. Here, we computationally predict and experimentally validate a vectorial hierarchy of folding resolved at the atomistic level, where early intermediates are stabilized through non-native hydrophobic interactions before rearranging into the native-like fold. Disrupting these interactions destabilizes intermediates and impairs folding. The chaperone trigger factor alters the cotranslational folding pathway by keeping the nascent peptide dynamic until the full domain emerges. Our results highlight an unexpected role of surface-exposed residues in protein folding on the ribosome and provide tools to improve folding prediction and protein design.Early folding intermediates form via non-native contacts and are reshaped by chaperones during protein synthesis on the ribosome.Cotranslational protein folding follows a distinct pathway shaped by the vectorial emergence of the peptide and spatial constraints of the ribosome exit tunnel. Variations in translation rhythm can cause misfolding linked to disease; however, predicting cotranslational folding pathways remains challenging. Here, we computationally predict and experimentally validate a vectorial hierarchy of folding resolved at the atomistic level, where early intermediates are stabilized through non-native hydrophobic interactions before rearranging into the native-like fold. Disrupting these interactions destabilizes intermediates and impairs folding. The chaperone trigger factor alters the cotranslational folding pathway by keeping the nascent peptide dynamic until the full domain emerges. Our results highlight an unexpected role of surface-exposed residues in protein folding on the ribosome and provide tools to improve folding prediction and protein design.Early folding intermediates form via non-native contacts and are reshaped by chaperones during protein synthesis on the ribosome
Going 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
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Protein folding and misfolding in the cell: towards an atomistic picture
No full textProteins, the molecules that perform the majority of tasks required to sustain life at the molecular level, must generally fold into a specific structure in order to perform their molecular functions. Despite decades of research, we do not fully understand how proteins fold up into their correct structures, starting off as a linear chain of amino acids, while avoiding incorrect misfolded structures linked to diseases such as Alzheimer's, Parkinson's, and various forms of cancer. It was previously believed that most proteins can autonomously fold into their native structures, driven by the physical and chemical interactions between a protein's constituent amino acids. But growing evidence suggests that, for a large number of proteins, these interactions instead cause the chain to misfold into nonnative structures, thus necessitating the assistance of additional cellular mechanisms to ensure the correct native state is attained. For instance, in the cell many proteins can start to fold as they are being synthesized on the ribosome. Previous studies have demonstrated that this process, known as co-translational folding, can significantly improve the native folding efficiency for many proteins that cannot efficiently fold autonomously.
Furthermore, recent bioinformatics studies have shown that, in many organisms, co-translational folding tends to begin at nascent chain lengths associated with evolutionarily conserved, slowly translating codons, suggesting that it is widely beneficial to slow down synthesis and give proteins time to fold co-translationally.
But the precise molecular mechanisms through which co-translational folding helps proteins efficiently reach their native state and avoid detrimental misfolded states, remains poorly understood, largely owing to immense technical difficulties in studying this highly dynamic process. Such an understanding is necessary if we are to rationally manipulate protein quality control mechanisms in the cell to alleviate misfolding diseases.
The goal of this dissertation is to develop and apply novel interdisciplinary pipeline, combining theory, atomistic simulation, and in vitro experiments to elucidate, at the molecular level, why certain proteins which face difficulty folding autonomously can reach their native states much more efficiently via co-translational folding. In Chapter 1, we present a novel algorithm, known as DBFOLD, that uses atomistic Monte-Carlo simulation, machine-learning based analysis, and statistical physics theory to predict detailed folding pathways and rates for large proteins while accounting for the possibility of non-native misfolding--a crucial feature omitted from many existing atomistic simulation algorithms for the sake of computational feasibility. In Chapter 2, we apply the DBFOLD algorithm to predict the co-translational folding mechanisms
of certain E. coli proteins with conserved clusters of slow codons and to explain why these proteins benefit from folding co-translationally. We find that, for these proteins, there is a narrow window of intermediate translation lengths at which native-like folding is both thermodynamically favorable and kinetically fast. But beyond these lengths, folding kinetics slow down by orders of magnitude due to deep nonnative traps stabilized by newly-synthesized C-terminal residues. Thus, co-translational folding is predicted to help these proteins circumvent deep kinetic traps and rapidly reach their native state--strategically-evolved slow codons at these lengths can give the nascent chain additional time to take advantage of these optimal folding windows.
A key advantage of our atomistic simulations is that they generate highly, specific, experimentally testable predictions. In Chapter 3, we test these predictions as they apply to E. coli MarR, one of the proteins predicted to circumvent deep folding traps via co-translational folding. Using in vitro refolding and mutagenesis experiments, we confirm the existence of these trapped states and preliminarily show that the simulations can accurately predict their structure and underlying molecular interactions. Our experiments thus lend support to our atomistic model for the MarR folding landscape, and indirectly support the predicted mechanism by which co-translational folding may allow folding traps to be circumvented. The work also sheds light on evolutionary tradeoffs that MarR faces between various biophysical properties under selection.
Finally in Chapter 4, we apply our combined computational/experimental methodology to investigate the folding mechanism of the receptor binding domain (RBD) of the SARS-CoV-2--the virus behind the Covid-19 pandemic--with the ultimate goal of linking biophysical folding properties to viral fitness and pathology. We find that the RBD can only refold reversibly if its disulfides are kept intact during denaturation, whereas their disruption leads to spontaneous misfolding into a molten-globule like nonnative state which is highly aggregation-prone. But our simulations predict that the RBD can solve this problem by folding co-translationally during secretion in to the endoplasmic reticulum--this process is predicted to increase the odds that the correct disulfides form and ultimately lock the protein into its native state, thus minimizing nonnative misfolding.
Together, these results present and validate a novel interdisciplinary pipeline that significantly advances our detailed molecular understanding of co-translational protein folding in the cell--a process long known to be beneficial albeit through poorly understood mechanisms. We expect that future work will continue probing the detailed molecular models generated here, along with their crucial evolutionary and biomedical implications
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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