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  1. Article ; Online: Computational evidences of a misfolding event in an aggregation-prone light chain preceding the formation of the non-native pathogenic dimer.

    Desantis, Fausta / Miotto, Mattia / Milanetti, Edoardo / Ruocco, Giancarlo / Di Rienzo, Lorenzo

    Proteins

    2024  

    Abstract: Antibody light chain amyloidosis is a disorder in which protein aggregates, mainly composed of immunoglobulin light chains, deposit in diverse tissues impairing the correct functioning of organs. Interestingly, due to the high susceptibility of ... ...

    Abstract Antibody light chain amyloidosis is a disorder in which protein aggregates, mainly composed of immunoglobulin light chains, deposit in diverse tissues impairing the correct functioning of organs. Interestingly, due to the high susceptibility of antibodies to mutations, AL amyloidosis appears to be strongly patient-specific. Indeed, every patient will display their own mutations that will make the proteins involved prone to aggregation thus hindering the study of this disease on a wide scale. In this framework, determining the molecular mechanisms that drive the aggregation could pave the way to the development of patient-specific therapeutics. Here, we focus on a particular patient-derived light chain, which has been experimentally characterized. We investigated the early phases of the aggregation pathway through extensive full-atom molecular dynamics simulations, highlighting a structural rearrangement and the exposure of two hydrophobic regions in the aggregation-prone species. Next, we moved to consider the pathological dimerization process through docking and molecular dynamics simulations, proposing a dimeric structure as a candidate pathological first assembly. Overall, our results shed light on the first phases of the aggregation pathway for a light chain at an atomic level detail, offering new structural insights into the corresponding aggregation process.
    Language English
    Publishing date 2024-02-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.26672
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2291: Show issues Location:
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  2. Article ; Online: Computational Approaches to Predict Protein-Protein Interactions in Crowded Cellular Environments.

    Grassmann, Greta / Miotto, Mattia / Desantis, Fausta / Di Rienzo, Lorenzo / Tartaglia, Gian Gaetano / Pastore, Annalisa / Ruocco, Giancarlo / Monti, Michele / Milanetti, Edoardo

    Chemical reviews

    2024  Volume 124, Issue 7, Page(s) 3932–3977

    Abstract: Investigating 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 ...

    Abstract Investigating 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.
    MeSH term(s) Humans ; Molecular Dynamics Simulation ; Proteins/chemistry ; Cell Communication ; Biophysical Phenomena
    Chemical Substances Proteins
    Language English
    Publishing date 2024-03-27
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 207949-5
    ISSN 1520-6890 ; 0009-2665
    ISSN (online) 1520-6890
    ISSN 0009-2665
    DOI 10.1021/acs.chemrev.3c00550
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  3. Article ; Online: Dynamical changes of SARS-CoV-2 spike variants in the highly immunogenic regions impact the viral antibodies escaping.

    Di Rienzo, Lorenzo / Miotto, Mattia / Desantis, Fausta / Grassmann, Greta / Ruocco, Giancarlo / Milanetti, Edoardo

    Proteins

    2023  Volume 91, Issue 8, Page(s) 1116–1129

    Abstract: The prolonged circulation of the SARS-CoV-2 virus resulted in the emergence of several viral variants, with different spreading features. Moreover, the increased number of recovered and/or vaccinated people introduced a selective pressure toward variants ...

    Abstract The prolonged circulation of the SARS-CoV-2 virus resulted in the emergence of several viral variants, with different spreading features. Moreover, the increased number of recovered and/or vaccinated people introduced a selective pressure toward variants able to evade the immune system, developed against the former viral versions. This process results in reinfections. Aiming to study the latter process, we first collected a large structural dataset of antibodies in complex with the original version of SARS-CoV-2 Spike protein. We characterized the peculiarities of such antibodies population with respect to a control dataset of antibody-protein complexes, highlighting some statistically significant differences between these two sets of antibodies. Thus, moving our attention to the Spike side of the complexes, we identify the Spike region most prone to interaction with antibodies, describing in detail also the energetic mechanisms used by antibodies to recognize different epitopes. In this framework, fast protocols able to assess the effect of novel mutations on the cohort of developed antibodies would help establish the impact of the variants on the population. Performing a molecular dynamics simulation of the trimeric form of the SARS-CoV-2 Spike protein for the wild type and two variants of concern, that is, the Delta and Omicron variants, we described the physicochemical features and the conformational changes experienced locally by the variants with respect to the original version. Hence, combining the dynamical information with the structural study on the antibody-spike dataset, we quantitatively explain why the Omicron variant has a higher capability of escaping the immune system than the Delta variant, due to the higher conformational variability of the most immunogenic regions. Overall, our results shed light on the molecular mechanism behind the different responses the SARS-CoV-2 variants display against the immune response induced by either vaccines or previous infections. Moreover, our analysis proposes an approach that can be easily extended to both other SARS-CoV-2 variants or different molecular systems.
    MeSH term(s) Humans ; Antibodies, Viral ; SARS-CoV-2/genetics ; COVID-19 ; Antibodies, Neutralizing
    Chemical Substances Antibodies, Viral ; spike protein, SARS-CoV-2 ; Antibodies, Neutralizing
    Language English
    Publishing date 2023-04-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 806683-8
    ISSN 1097-0134 ; 0887-3585
    ISSN (online) 1097-0134
    ISSN 0887-3585
    DOI 10.1002/prot.26497
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2291: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Spatial organization of hydrophobic and charged residues affects protein thermal stability and binding affinity.

    Desantis, Fausta / Miotto, Mattia / Di Rienzo, Lorenzo / Milanetti, Edoardo / Ruocco, Giancarlo

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 12087

    Abstract: What are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are two major questions of molecular biology, whose answers bring important implications both from a theoretical and ... ...

    Abstract What are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are two major questions of molecular biology, whose answers bring important implications both from a theoretical and applicative point of view. Here, we analyze chemical and physical features on a large dataset of protein-protein complexes with reliable experimental binding affinity data and compare them with a set of monomeric proteins for which melting temperature data was available. In particular, we probed the spatial organization of protein (1) intramolecular and intermolecular interaction energies among residues, (2) amino acidic composition, and (3) their hydropathy features. Analyzing the interaction energies, we found that strong Coulombic interactions are preferentially associated with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with stronger protein-protein binding affinity. Statistical analysis of amino acids abundances, exposed to the molecular surface and/or in interaction with the molecular partner, confirmed that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. Leveraging on the important role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces in the binding regions and evaluated their shape complementarity, decomposing the molecular patches in the 2D Zernike basis. For the first time, we quantified the correlation between local shape complementarity and binding affinity via the Zernike formalism. In addition, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary as much as the correlation between van der Waals energy and binding affinity. In turn, these relationships 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.
    MeSH term(s) Amino Acids/chemistry ; Hydrophobic and Hydrophilic Interactions ; Membrane Proteins ; Protein Binding ; Protein Stability ; Thermodynamics
    Chemical Substances Amino Acids ; Membrane Proteins
    Language English
    Publishing date 2022-07-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-16338-5
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  5. Article: Differences in the organization of interface residues tunes the stability of the SARS-CoV-2 spike-ACE2 complex.

    Miotto, Mattia / Di Rienzo, Lorenzo / Grassmann, Greta / Desantis, Fausta / Cidonio, Gianluca / Gosti, Giorgio / Leonetti, Marco / Ruocco, Giancarlo / Milanetti, Edoardo

    Frontiers in molecular biosciences

    2023  Volume 10, Page(s) 1205919

    Abstract: The 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 ... ...

    Abstract The 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.
    Language English
    Publishing date 2023-06-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2023.1205919
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  6. Book ; Online: Investigating the side-chain structural organization behind the stability of protein folding and binding

    Desantis, Fausta / Miotto, Mattia / Di Rienzo, Lorenzo / Milanetti, Edoardo / Ruocco, Giancarlo

    2021  

    Abstract: What 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 ... ...

    Abstract What 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 figures
    Keywords Physics - Biological Physics ; Physics - Chemical Physics
    Subject code 612
    Publishing date 2021-07-16
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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