1,720,958 research outputs found
Differences in the organization of interface residues tunes the stability of the sars-cov-2 spike-ace2 complex
Full text linkThe continuous emergence of novel variants represents one of the major problems in dealing with the SARS-CoV-2 virus. Indeed, also due to its prolonged circulation, more than ten variants of concern emerged, each time rapidly overgrowing the current viral version due to improved spreading features. As, up to now, all variants carry at least one mutation on the spike Receptor Binding Domain, the stability of the binding between the SARS-CoV-2 spike protein and the human ACE2 receptor seems one of the molecular determinants behind the viral spreading potential. In this framework, a better understanding of the interplay between spike mutations and complex stability can help to assess the impact of novel variants. Here, we characterize the peculiarities of the most representative variants of concern in terms of the molecular interactions taking place between the residues of the spike RBD and those of the ACE2 receptor. To do so, we performed molecular dynamics simulations of the RBD-ACE2 complexes of the seven variants of concern in comparison with a large set of complexes with different single mutations taking place on the RBD solvent-exposed residues and for which the experimental binding affinity was available. Analyzing the strength and spatial organization of the intermolecular interactions of the binding region residues, we found that (i) mutations producing an increase of the complex stability mainly rely on instaurating more favorable van der Waals optimization at the cost of Coulombic ones. In particular, (ii) an anti-correlation is observed between the shape and electrostatic complementarities of the binding regions. Finally, (iii) we showed that combining a set of dynamical descriptors is possible to estimate the outcome of point mutations on the complex binding region with a performance of 0.7. Overall, our results introduce a set of dynamical observables that can be rapidly evaluated to probe the effects of novel isolated variants or different molecular systems
Computational Approaches to Predict Protein–Protein Interactions in Crowded Cellular Environments
Full text linkInvestigating protein–protein interactions is crucial for understanding cellular biological processes because proteins often function within molecular complexes rather than in isolation. While experimental and computational methods have provided valuable insights into these interactions, they often overlook a critical factor: the crowded cellular environment. This environment significantly impacts protein behavior, including structural stability, diffusion, and ultimately the nature of binding. In this review, we discuss theoretical and computational approaches that allow the modeling of biological systems to guide and complement experiments and can thus significantly advance the investigation, and possibly the predictions, of protein–protein interactions in the crowded environment of cell cytoplasm. We explore topics such as statistical mechanics for lattice simulations, hydrodynamic interactions, diffusion processes in high-viscosity environments, and several methods based on molecular dynamics simulations. By synergistically leveraging methods from biophysics and computational biology, we review the state of the art of computational methods to study the impact of molecular crowding on protein–protein interactions and discuss its potential revolutionizing effects on the characterization of the human interactome
Investigating the side-chain structural organization behind the stability of protein folding and binding
Full text linkWhat are the molecular mechanisms that dictate protein-protein binding
stability and whether those are related to the ones behind protein fold
stability are still largely open questions. Indeed, despite many past efforts,
we still lack definitive models to account for experimental quantities like
protein melting temperature or complex binding affinity. Here, we investigate
and compare chemical and physical features on a dataset of protein with known
melting temperature as well as a large dataset of protein-protein complexes
with reliable experimental binding affinity. In particular, we probed the
aminoacid composition and the organization of the network of intramolecular and
intermolecular interaction energies among residues.
We found that hydrophobic residues present on the protein surfaces are
preferentially located in the binding regions, while charged residues behave
oppositely. In addition, the abundance of polar amino acid like Serine and
Proline correlates with the binding affinity of the complexes. Analysing the
interaction energies we found that distant Coulombic interactions are
responsible for thermal stability while the total inter-molecular van der Waals
energy correlates with protein-protein binding affinity.Comment: 8 pages, 3 figure
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Refining proteins interactions to tackle aggregation in AL amyloidosis via the computational design of inhibitory peptides
Full text linkProteins are biomolecules at the base of most fundamental processes in living organisms, ranging from cellular architecture to signal transduction, biosynthesis, regulatory pathways, immune response, etc. Although they can stand in an unbound configuration within the cell, the importance of their role emerges when they interact with ligands like other proteins. Therefore, understanding the mechanisms underpinning protein structural and interaction stability can provide insight into the functioning of the cellular machinery. This project first undertakes the study of such properties by comparing the role of non-bonded interactions (i.e. Coulombic and van der Waals potentials) with respect to the melting temperature and the binding affinity, two widely referenced experimental descriptors of protein folding and association stability, respectively.
The protocols developed and the conclusions drawn in this phase were then probed in the investigation of two cases in which protein-protein interactions result in pathological scenarios, namely SARS-CoV-2 and AL amyloidosis.
As for SARS-Cov-2, my contribution encompassed the calculation of non-bonded interactions and investigating their role in determining binding stability in the Spike-ACE2 and Spike-antibody complexes in relation to the physicochemical features of the mutated residues in viral variants and the immunogenicity of the Spike protein surface.
Coming to AL amyloidosis, this is a highly patient-specific condition associated with the aggregation and deposition of immunoglobulin light chains resulting in organ failure. We focused on a mutated patient-derived aggregation-prone light chain and its non-aggregating germ-line counterpart and performed extensive molecular dynamics simulations, highlighting misfolding in the pathogenic monomer. Applying docking procedures to the misfolded configuration, we proposed the structure of a putative pathogenic dimer. We then moved to look for a peptide candidate for binding hindrance using a Monte Carlo-based mutagenesis protocol. Affinity calculations confirmed that the optimised peptide thus obtained could be a good competitor against pathogenic dimerisation
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Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity
Full text linkWhat are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are key issues in molecular biology having important implications both under a theoretical and an applicative perspective. Here, we analyze chemico-physical features on a large dataset of protein-protein complexes of known experimental binding affinity data and compare them with a set of monomeric proteins of available melting temperature data. Firstly, we probed the spatial organization of protein intra- and inter-molecular interaction energies among residues showing that strong Coulombic interactions associate with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with protein-protein binding affinity. Given the role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces of the binding regions and evaluated their shape complementarity, employing a 2D Zernike polynomials expansion, thus managing to quantify the correlation between local shape complementarity and binding affinity. Moreover, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary. These results pave the way to the fast and accurate prediction and design of optimal binding regions as the 2D Zernike formalism allows a rapid and superposition-free comparison between possible binding surfaces
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
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