Exploring the unbinding ofLeishmania(L.)amazonensisCPB derived-epitopes from H2 MHC class I proteins

Brandt, Artur A M L; Batista, Paulo Ricardo; Souza-Silva, Franklin; Alves, Carlos Roberto; Caffarena, Ernesto R.

doi:10.1002/prot.24994

Cited by 15 publications

(16 citation statements)

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“…In previous work, our results suggested a behavior pattern for peptides that bind H-2 receptors [31]. Those results were obtained assuming a preset condition for the parameters used to perform enhanced sampling simulations.…”

Section: Discussionsupporting

confidence: 66%

Combining Well‐Tempered Metadynamics Simulation and SPR Assays to Characterize the Binding Mechanism of the Universal T‐Lymphocyte Tetanus Toxin Epitope TT830‐843

Brandt

Rodrigues-da-Silva

Lima-Junior

et al. 2021

BioMed Research International

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Peptide TT830-843 from the tetanus toxin is a universal T-cell epitope. It helps in vaccination and induces T-cell activation. However, the fine molecular interaction between this antigen and the major histocompatibility complex (MHC) remains unknown. Molecular analysis of its interaction with murine MHC (H-2) was proposed to explore its immune response efficiency. Molecular dynamics simulations are important mechanisms for understanding the basis of protein-ligand interactions, and metadynamics is a useful technique for enhancing sampling in molecular dynamics. SPR (surface plasmon resonance) assays were used to validate whether the metadynamics results are in accordance with the experimental results. The peptide TT830-843 unbinding process was simulated, and the free energy surface reconstruction revealed a detailed conformational landscape. The simulation described the exiting path as a stepwise mechanism between progressive detachment states. We pointed out how the terminus regions act as anchors for binding and how the detachment mechanism includes the opening of α-helices to permit the peptide’s central region dissociation. The results indicated the peptide/H-2 receptor encounter occurs within a distance lesser than 27.5 Å, and the encounter can evolve to form a stable complex. SPR assays confirmed the complex peptide/H-2 as a thermodynamically stable system, exhibiting enough free energy to interact with TCR on the antigen-presenting cell surface. Therefore, combining in silico and in vitro assays provided significant evidence to support the peptide/H-2 complex formation.

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Section: Discussionsupporting

confidence: 66%

Combining Well‐Tempered Metadynamics Simulation and SPR Assays to Characterize the Binding Mechanism of the Universal T‐Lymphocyte Tetanus Toxin Epitope TT830‐843

Brandt

Rodrigues-da-Silva

Lima-Junior

et al. 2021

BioMed Research International

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“…The nAPOLI analyses revealed hydrophobic contacts among only four SARS-CoV ligands (PDB codes 3V3M, 4TWW, 4TWY, 5C5O) and Ala46. However, previous studies have suggested a substantial indirect influence of this substitution at the active site entrance dynamics (Brandt et al., 2016 ; Domingo et al., 2016 ). Indeed, analysis of the crystallographic B-factors at different M CoV2 pro complexes points to the loop 44–53 at domain I and its neighbor, the loop 184–193 at domain II, as mobility hotspots at the enzyme active site ( Figure 2(B) ).…”

Section: Resultsmentioning

confidence: 91%

“…The equations for MetaDy projections were used similarly to Brandt et al. ( 2016 ). Similarly to recent works of our group, we used the colony method adapted by Martínez et al.…”

Section: Theoretical Methodsmentioning

confidence: 99%

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A higher flexibility at the SARS-CoV-2 main protease active site compared to SARS-CoV and its potentialities for new inhibitor virtual screening targeting multi-conformers

Rocha

Chaves

Fischer

et al. 2021

Journal of Biomolecular Structure and Dynamics

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The main-protease (M pro ) catalyzes a crucial step for the SARS-CoV-2 life cycle. The recent SARS-CoV-2 presents the main protease (M CoV2 pro ) with 12 mutations compared to SARS-CoV (M CoV1 pro ). Recent studies point out that these subtle differences lead to mobility variances at the active site loops with functional implications. We use metadynamics simulations and a sort of computational analysis to probe the dynamic, pharmacophoric and catalytic environment differences between the monomers of both enzymes. So, we verify how much intrinsic distinctions are preserved in the functional dimer of M CoV2 pro , as well as its implications for ligand accessibility and optimized drug screening. We find a significantly higher accessibility to open binding conformers in the M CoV2 pro monomer compared to M CoV1 pro . A higher hydration propensity for the M CoV2 pro S2 loop with the A46S substitution seems to exercise a key role. Quantum calculations suggest that the wider conformations for M CoV2 pro are less catalytically active in the monomer. However, the statistics for contacts involving the N-finger suggest higher maintenance of this activity at the dimer. Docking analyses suggest that the ability to vary the active site width can be important to improve the access of the ligand to the active site in different ways. So, we carry out a multiconformational virtual screening with different ligand bases. The results point to the importance of taking into account the protein conformational multiplicity for new promissors anti M CoV2 pro ligands. We hope these results will be useful in prospecting, repurposing and/or designing new anti SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma

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“…It could be obtained a significant convergence for the MetaD recovered values for each system in our protocol, with maximal standard deviation of 1.57 kcal for the systems 1lvm (chain D), 1lvb (chain D) and 2q6g (chain C) and a relatively higher deviation of 4.32 kcal just for 1uk4. In fact, such convergence is not surprising, once the already consolidated situation of the metadynamics technique as an accurate computational tool to estimate the binding free energy for usual ligands and peptides, being a powerful method on drug screening procedures [ 48 – 50 ]. The accuracy of this technique, in this way, makes it a providential instrument to validate the Propedia methodology at the screening of peptides with differential affinities for the Sars-Cov-2 MPro, given the still sparse availability of experimental data for peptide affinity at this new and important target.…”

Section: Utility and Discussionmentioning

confidence: 99%

Propedia: a database for protein–peptide identification based on a hybrid clustering algorithm

et al. 2021

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Background Protein–peptide interactions play a fundamental role in a wide variety of biological processes, such as cell signaling, regulatory networks, immune responses, and enzyme inhibition. Peptides are characterized by low toxicity and small interface areas; therefore, they are good targets for therapeutic strategies, rational drug planning and protein inhibition. Approximately 10% of the ethical pharmaceutical market is protein/peptide-based. Furthermore, it is estimated that 40% of protein interactions are mediated by peptides. Despite the fast increase in the volume of biological data, particularly on sequences and structures, there remains a lack of broad and comprehensive protein–peptide databases and tools that allow the retrieval, characterization and understanding of protein–peptide recognition and consequently support peptide design. Results We introduce Propedia, a comprehensive and up-to-date database with a web interface that permits clustering, searching and visualizing of protein–peptide complexes according to varied criteria. Propedia comprises over 19,000 high-resolution structures from the Protein Data Bank including structural and sequence information from protein–peptide complexes. The main advantage of Propedia over other peptide databases is that it allows a more comprehensive analysis of similarity and redundancy. It was constructed based on a hybrid clustering algorithm that compares and groups peptides by sequences, interface structures and binding sites. Propedia is available through a graphical, user-friendly and functional interface where users can retrieve, and analyze complexes and download each search data set. We performed case studies and verified that the utility of Propedia scores to rank promissing interacting peptides. In a study involving predicting peptides to inhibit SARS-CoV-2 main protease, we showed that Propedia scores related to similarity between different peptide complexes with SARS-CoV-2 main protease are in agreement with molecular dynamics free energy calculation. Conclusions Propedia is a database and tool to support structure-based rational design of peptides for special purposes. Protein–peptide interactions can be useful to predict, classifying and scoring complexes or for designing new molecules as well. Propedia is up-to-date as a ready-to-use webserver with a friendly and resourceful interface and is available at: https://bioinfo.dcc.ufmg.br/propedia

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Exploring the unbinding ofLeishmania(L.)amazonensisCPB derived-epitopes from H2 MHC class I proteins

Cited by 15 publications

References 50 publications

Combining Well‐Tempered Metadynamics Simulation and SPR Assays to Characterize the Binding Mechanism of the Universal T‐Lymphocyte Tetanus Toxin Epitope TT830‐843

Combining Well‐Tempered Metadynamics Simulation and SPR Assays to Characterize the Binding Mechanism of the Universal T‐Lymphocyte Tetanus Toxin Epitope TT830‐843

A higher flexibility at the SARS-CoV-2 main protease active site compared to SARS-CoV and its potentialities for new inhibitor virtual screening targeting multi-conformers

Propedia: a database for protein–peptide identification based on a hybrid clustering algorithm

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