scholarly journals Shedding Light on the Molecular Recognition of Sub-Kilodalton Macrocyclic Peptides on Thrombin by Supervised Molecular Dynamics

2021 ◽  
Vol 8 ◽  
Author(s):  
Mahdi Hassankalhori ◽  
Giovanni Bolcato ◽  
Maicol Bissaro ◽  
Mattia Sturlese ◽  
Stefano Moro
Keyword(s):  
Molecular Dynamics ◽  
Molecular Recognition ◽  
Protein Interactions ◽  
Binding Mode ◽  
Structural Features ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
New Class ◽  
Macrocyclic Peptides ◽  
Simulation Time

Macrocycles are attractive structures for drug development due to their favorable structural features, potential in binding to targets with flat featureless surfaces, and their ability to disrupt protein–protein interactions. Moreover, large novel highly diverse libraries of low-molecular-weight macrocycles with therapeutically favorable characteristics have been recently established. Considering the mentioned facts, having a validated, fast, and accurate computational protocol for studying the molecular recognition and binding mode of this interesting new class of macrocyclic peptides deemed to be helpful as well as insightful in the quest of accelerating drug discovery. To that end, the ability of the in-house supervised molecular dynamics protocol called SuMD in the reproduction of the X-ray crystallography final binding state of a macrocyclic non-canonical tetrapeptide—from a novel library of 8,988 sub-kilodalton macrocyclic peptides—in the thrombin active site was successfully validated. A comparable binding mode with the minimum root-mean-square deviation (RMSD) of 1.4 Å at simulation time point 71.6 ns was achieved. This method validation study extended the application domain of the SuMD sampling method for computationally cheap, fast but accurate, and insightful macrocycle–protein molecular recognition studies.

scholarly journals Structural Features of Tight-Junction Proteins

2019 ◽  
Vol 20 (23) ◽  
pp. 6020 ◽  
Author(s):  
Udo Heinemann ◽  
Anja Schuetz
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Protein Interactions ◽  
Three Dimensional ◽  
Structural Features ◽  
Resonance Spectroscopy ◽  
Tight Junction Proteins ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
Junction Proteins

Tight junctions are complex supramolecular entities composed of integral membrane proteins, membrane-associated and soluble cytoplasmic proteins engaging in an intricate and dynamic system of protein–protein interactions. Three-dimensional structures of several tight-junction proteins or their isolated domains have been determined by X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy. These structures provide direct insight into molecular interactions that contribute to the formation, integrity, or function of tight junctions. In addition, the known experimental structures have allowed the modeling of ligand-binding events involving tight-junction proteins. Here, we review the published structures of tight-junction proteins. We show that these proteins are composed of a limited set of structural motifs and highlight common types of interactions between tight-junction proteins and their ligands involving these motifs.

scholarly journals Structural features underlying the activity of benzimidazole derivatives that target phosphopeptide recognition by the tandem BRCT domain of the BRCA1 protein

2019 ◽  
Author(s):  
Vadiraj Kurdekar ◽  
Saranya Giridharan ◽  
Jasti Subbarao ◽  
Mamatha B. Nijaguna ◽  
Jayaprakash Periasamy ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Interactions ◽  
Binding Mode ◽  
Structural Features ◽  
Benzimidazole Derivatives ◽  
Protein Protein Interactions ◽  
Brca1 Protein ◽  
Cellular Assays ◽  
Intracellular Signals ◽  
Combine Structure

AbstractThe tandem BRCT (tBRCT) domains of BRCA1 engage pSer-containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, a benzimidazole that represents a first selective small molecule inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domains, which selectively interrupts BRCA1-mediated cellular responses evoked by DNA damage. Here, we combine structure-guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features that underlie the biochemical and cellular activities of Bractoppin. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing single residue substitutions that alter K1702, a key residue mediating phosphopeptide recognition (K1702A), or alter hydrophobic residues (F1662R or L1701K) that adjoin the pSer-recognition site. However, mutation of BRCA1 tBRCT residue M1775R, which engages the Phe residue in the consensus phosphopeptide motif pSer-X-X-Phe, does not affect Bractoppin binding. Collectively, these findings confirm a binding mode for Bractoppin that blocks the phosphopeptide-binding site via structural features distinct from the substrate phosphopeptide. We explored these structural features through structure-guided chemical elaboration of Bractoppin, synthesizing analogs bearing modifications on the left and right hand side (LHS/RHS) of Bractoppin’s benzimidazole ring. Characterization of these analogs in biochemical assay reveal structural features underlying potency. Analogs where the LHS phenyl is replaced by cyanomethyl (2091) and 4-methoxyphenoxypropyl (2113) conceptualized from structure-guided strategies like GIST and dimer interface analysis expose the role of phenyl and isopropyl as critical hydrophobic anchors. Two Bractoppin analogs, 2088 and 2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the biochemical and cellular activity of a novel benzimidazole inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target the protein-protein interactions of this previously undrugged family of protein domains.

Protein Interaction Domains and Post-Translational Modifications: Structural Features and Drug Discovery Applications

2020 ◽  
Vol 27 (37) ◽  
pp. 6306-6355 ◽  
Author(s):  
Marian Vincenzi ◽  
Flavia Anna Mercurio ◽  
Marilisa Leone
Keyword(s):  
Drug Discovery ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Structural Information ◽  
Protein Complexes ◽  
Structural Features ◽  
Protein Protein Interactions ◽  
Modular Architecture ◽  
Post Translational Modifications ◽  
Interaction Domains

Background:: Many pathways regarding healthy cells and/or linked to diseases onset and progression depend on large assemblies including multi-protein complexes. Protein-protein interactions may occur through a vast array of modules known as protein interaction domains (PIDs). Objective:: This review concerns with PIDs recognizing post-translationally modified peptide sequences and intends to provide the scientific community with state of art knowledge on their 3D structures, binding topologies and potential applications in the drug discovery field. Method:: Several databases, such as the Pfam (Protein family), the SMART (Simple Modular Architecture Research Tool) and the PDB (Protein Data Bank), were searched to look for different domain families and gain structural information on protein complexes in which particular PIDs are involved. Recent literature on PIDs and related drug discovery campaigns was retrieved through Pubmed and analyzed. Results and Conclusion:: PIDs are rather versatile as concerning their binding preferences. Many of them recognize specifically only determined amino acid stretches with post-translational modifications, a few others are able to interact with several post-translationally modified sequences or with unmodified ones. Many PIDs can be linked to different diseases including cancer. The tremendous amount of available structural data led to the structure-based design of several molecules targeting protein-protein interactions mediated by PIDs, including peptides, peptidomimetics and small compounds. More studies are needed to fully role out, among different families, PIDs that can be considered reliable therapeutic targets, however, attacking PIDs rather than catalytic domains of a particular protein may represent a route to obtain selective inhibitors.

Decoding Protein-protein Interactions: An Overview

2020 ◽  
Vol 20 (10) ◽  
pp. 855-882
Author(s):  
Olivia Slater ◽  
Bethany Miller ◽  
Maria Kontoyianni
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Drug Repurposing ◽  
Protein Docking ◽  
Target Space ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
Protein Protein Interaction ◽  
Interaction Sites ◽  
Long Time

Drug discovery has focused on the paradigm “one drug, one target” for a long time. However, small molecules can act at multiple macromolecular targets, which serves as the basis for drug repurposing. In an effort to expand the target space, and given advances in X-ray crystallography, protein-protein interactions have become an emerging focus area of drug discovery enterprises. Proteins interact with other biomolecules and it is this intricate network of interactions that determines the behavior of the system and its biological processes. In this review, we briefly discuss networks in disease, followed by computational methods for protein-protein complex prediction. Computational methodologies and techniques employed towards objectives such as protein-protein docking, protein-protein interactions, and interface predictions are described extensively. Docking aims at producing a complex between proteins, while interface predictions identify a subset of residues on one protein that could interact with a partner, and protein-protein interaction sites address whether two proteins interact. In addition, approaches to predict hot spots and binding sites are presented along with a representative example of our internal project on the chemokine CXC receptor 3 B-isoform and predictive modeling with IP10 and PF4.

scholarly journals Protein–Protein Interactions in Translesion Synthesis

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5544
Author(s):  
Radha Charan Dash ◽  
Kyle Hadden
Keyword(s):  
Protein Interactions ◽  
Acquired Resistance ◽  
Translesion Synthesis ◽  
Initial Response ◽  
Structural Features ◽  
Dna Lesions ◽  
Protein Protein Interactions ◽  
Dna Damage Tolerance ◽  
Response To Chemotherapy ◽  
Depth Analysis

Translesion synthesis (TLS) is an error-prone DNA damage tolerance mechanism used by actively replicating cells to copy past DNA lesions and extend the primer strand. TLS ensures that cells continue replication in the presence of damaged DNA bases, albeit at the expense of an increased mutation rate. Recent studies have demonstrated a clear role for TLS in rescuing cancer cells treated with first-line genotoxic agents by allowing them to replicate and survive in the presence of chemotherapy-induced DNA lesions. The importance of TLS in both the initial response to chemotherapy and the long-term development of acquired resistance has allowed it to emerge as an interesting target for small molecule drug discovery. Proper TLS function is a complicated process involving a heteroprotein complex that mediates multiple attachment and switching steps through several protein–protein interactions (PPIs). In this review, we briefly describe the importance of TLS in cancer and provide an in-depth analysis of key TLS PPIs, focusing on key structural features at the PPI interface while also exploring the potential druggability of each key PPI.

scholarly journals Crystal structure and functional implication of bacterial STING

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Tzu-Ping Ko ◽  
Yu-Chuan Wang ◽  
Chia-Shin Yang ◽  
Mei-Hui Hou ◽  
Chao-Jung Chen ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Driving Force ◽  
Binding Mode ◽  
Innate Immune ◽  
Ligand Specificity ◽  
Protein Protein Interactions ◽  
Recognition Mechanism ◽  
Cyclic Dinucleotides ◽  
Phage Propagation ◽  
Complex Crystal

AbstractMammalian innate immune sensor STING (STimulator of INterferon Gene) was recently found to originate from bacteria. During phage infection, bacterial STING sense c-di-GMP generated by the CD-NTase (cGAS/DncV-like nucleotidyltransferase) encoded in the same operon and signal suicide commitment as a defense strategy that restricts phage propagation. However, the precise binding mode of c-di-GMP to bacterial STING and the specific recognition mechanism are still elusive. Here, we determine two complex crystal structures of bacterial STING/c-di-GMP, which provide a clear picture of how c-di-GMP is distinguished from other cyclic dinucleotides. The protein-protein interactions further reveal the driving force behind filament formation of bacterial STING. Finally, we group the bacterial STING into two classes based on the conserved motif in β-strand lid, which dictate their ligand specificity and oligomerization mechanism, and propose an evolution-based model that describes the transition from c-di-GMP-dependent signaling in bacteria to 2’3’-cGAMP-dependent signaling in eukaryotes.

scholarly journals Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions

2021 ◽  
Vol 17 (5) ◽  
pp. e1008988
Author(s):  
Nikolina ŠoŠtarić ◽  
Vera van Noort
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Structures ◽  
Cellular Protein ◽  
Free Energy Calculations ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Protein Properties ◽  
Dynamics Simulations

Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs’ effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.

scholarly journals Discovery, development and application of drugs targeting BCL-2 pro-survival proteins in cancer

2021 ◽  
Author(s):  
Erinna F. Lee ◽  
W. Douglas Fairlie
Keyword(s):  
Structural Biology ◽  
Protein Interactions ◽  
Basic Science ◽  
Great Success ◽  
Protein Protein Interactions ◽  
New Class ◽  
Success Stories ◽  
History Of ◽  
Approved Drugs ◽  
Close Relatives

The discovery of a new class of small molecule compounds that target the BCL-2 family of anti-apoptotic proteins is one of the great success stories of basic science leading to translational outcomes in the last 30 years. The eponymous BCL-2 protein was identified over 30 years ago due to its association with cancer. However, it was the unveiling of the biochemistry and structural biology behind it and its close relatives’ mechanism(s)-of-action that provided the inspiration for what are now known as ‘BH3-mimetics’, the first clinically approved drugs designed to specifically inhibit protein–protein interactions. Herein, we chart the history of how these drugs were discovered, their evolution and application in cancer treatment.

In silico specificity determination of neoantigen-reactive T-lymphocytes

2021 ◽  
Vol 67 (3) ◽  
pp. 251-258
Author(s):  
A.E. Kniga ◽  
I.V. Polyakov ◽  
A.V. Nemukhin
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Molecular Docking ◽  
Protein Interactions ◽  
Structural Features ◽  
Immune Recognition ◽  
Protein Protein Interactions ◽  
Binary Classifiers

Effective personalized immunotherapies of the future will need to capture not only the peculiarities of the patient’s tumor but also of his immune response to it. In this study, using results of in vitro high-throughput specificity assays, and combining comparative models of pMHCs and TCRs using molecular docking, we have constructed all-atom models for the putative complexes of all their possible pairwise TCR-pMHC combinations. For the models obtained we have calculated a dataset of physics-based scores and have trained binary classifiers that perform better compared to their solely sequence-based counterparts. These structure-based classifiers pinpoint the most prominent energetic terms and structural features characterizing the type of protein-protein interactions that underlies the immune recognition of tumors by T cells.

scholarly journals Mechanistic and Structural Insights on the IL-15 System through Molecular Dynamics Simulations

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3261
Author(s):  
Sousa ◽  
Laurent ◽  
Quéméner ◽  
Mortier ◽  
Questel
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Structural Features ◽  
Cellular Functions ◽  
Α Subunit ◽  
X Ray Crystallography ◽  
Receptor Complexes ◽  
Protein Interfaces ◽  
Dynamics Simulations ◽  
Comparison Of The Results

Interleukin 15 (IL-15), a four-helix bundle cytokine, is involved in a plethora of different cellular functions and, particularly, plays a key role in the development and activation of immune responses. IL-15 forms receptor complexes by binding with IL-2Rβ- and common γ(γc)-signaling subunits, which are shared with other members of the cytokines family (IL-2 for IL-2Rβ- and all other γc- cytokines for γc). The specificity of IL-15 is brought by the non-signaling α-subunit, IL-15Rα. Here we present the results of molecular dynamics simulations carried out on four relevant forms of IL-15: its monomer, IL-15 interacting individually with IL-15Rα (IL-15/IL-15Rα), with IL-2Rβ/γc subunits (IL-15/IL-2Rβ/γc) or with its three receptors simultaneously (IL-15/IL-15Rα/IL-2Rβ/γc). Through the analyses of the various trajectories, new insights on the structural features of the interfaces are highlighted, according to the considered form. The comparison of the results with the experimental data, available from X-ray crystallography, allows, in particular, the rationalization of the importance of IL-15 key residues (e.g. Asp8, Lys10, Glu64). Furthermore, the pivotal role of water molecules in the stabilization of the various protein-protein interfaces and their H-bonds networks are underlined for each of the considered complexes.

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