Computational design of Periplasmic binding protein biosensors guided by molecular dynamics.

Periplasmic binding proteins (PBPs) are bacterial proteins commonly used as scaffolds for substrate-detecting biosensors. In these biosensors, effector proteins (for example fluorescent proteins) are inserted into a PBP such that the effector protein's output changes upon PBP-substate binding. The insertion site is often determined by comparison of PBP apo/holo crystal structures, but random insertion libraries have shown that this can miss the best sites.

Synergizing Chemical Structures and Bioassay Descriptions for Enhanced Molecular Property Prediction in Drug Discovery.

The precise prediction of molecular properties can greatly accelerate the development of new drugs. However, molecular property prediction approaches have been limited so far to assays for which large amounts of data are available. In this study, we develop a new computational approach leveraging both the textual description of the assay of interest and the chemical structure of target compounds.

Neocarzilin Inhibits Cancer Cell Proliferation via BST-2 Degradation, Resulting in Lipid Raft-Trapped EGFR.

Neocarzilin (NCA) is a natural product exhibiting potent antimigratory as well as antiproliferative effects. While vesicle amine transport protein 1 (VAT-1) was previously shown to inhibit migration upon NCA binding, the molecular mechanisms responsible for impaired proliferation remained elusive. We here introduce a chemical probe closely resembling the structural and stereochemical features of NCA and unravel bone marrow stromal antigen 2 (BST-2) as one of the targets responsible for the antiproliferative effect of NCA in cancer cells.

Bacillamide D produced by Bacillus cereus from the mouse intestinal bacterial collection (miBC) is a potent cytotoxin in vitro.

The gut microbiota influences human health and the development of chronic diseases. However, our understanding of potentially protective or harmful microbe-host interactions at the molecular level is still in its infancy. To gain further insights into the hidden gut metabolome and its impact, we identified a cryptic non-ribosomal peptide BGC in the genome of Bacillus cereus DSM 28590 from the mouse intestine ( www.

Helical reorganization in the context of membrane protein folding: Insights from simulations with bacteriorhodopsin (BR) fragments.

Membrane protein folding is distinct from folding of soluble proteins. Conformational acquisition in major membrane protein subclasses can be delineated into insertion and folding processes. An exception to the "two stage" folding, later developed to "three stage" folding, is observed within the last two helices in bacteriorhodopsin (BR), a system that serves as a model membrane protein.

Structural Insights into Seeding Mechanisms of hIAPP Fibril Formation.

The deposition of islet amyloid polypeptide (hIAPP) fibrils is a hallmark of β-cell death in type II diabetes. In this study, we employ state-of-the-art MAS solid-state spectroscopy to investigate the previously elusive N-terminal region of hIAPP fibrils, uncovering both rigidity and heterogeneity. Comparative analysis between wild-type hIAPP and a disulfide-deficient variant (hIAPP) unveils shared fibril core structures yet strikingly distinct dynamics in the N-terminus.

Thermal Proteome Profiling Reveals Insight to Antiproliferative and Pro-Apoptotic Effects of Lagunamide A in the Modulation of DNA Damage Repair.

Lagunamide A is a biologically active natural product with a yet unidentified molecular mode of action. Cellular studies revealed that lagunamide A is a potent inhibitor of cancer cell proliferation, promotes apoptosis and causes mitochondrial dysfunction. To decipher the cellular mechanism responsible for these effects, we utilized thermal protein profiling (TPP) and identified EYA3 as a stabilized protein in cells upon lagunamide A treatment.

Machine Learning Assisted Hit Prioritization for High Throughput Screening in Drug Discovery.

Efficient prioritization of bioactive compounds from high throughput screening campaigns is a fundamental challenge for accelerating drug development efforts. In this study, we present the first data-driven approach to simultaneously detect assay interferents and prioritize true bioactive compounds. By analyzing the learning dynamics during training of a gradient boosting model on noisy high throughput screening data using a novel formulation of sample influence, we are able to distinguish between compounds exhibiting the desired biological response and those producing assay artifacts.

Structure-Based Protein Assembly Simulations Including Various Binding Sites and Conformations.

Many biological functions are mediated by large complexes formed by multiple proteins and other cellular macromolecules. Recent progress in experimental structure determination, as well as in integrative modeling and protein structure prediction using deep learning approaches, has resulted in a rapid increase in the number of solved multiprotein assemblies. However, the assembly process of large complexes from their components is much less well-studied.

Effectiveness of molecular fingerprints for exploring the chemical space of natural products.

Natural products are a diverse class of compounds with promising biological properties, such as high potency and excellent selectivity. However, they have different structural motifs than typical drug-like compounds, e.g.

Comprehensive Analysis of Coupled Proline Cis-Trans States in Bradykinin Using ωBP-REMD Simulations.

It is well-known that proline (Pro) cis-trans isomerization plays a decisive role in the folding and stabilization of proteins. The conformational coupling between isomerization states of different Pro residues in proteins during conformational adaptation processes is not well understood. In the present work, we investigate the coupled cis-trans isomerization of three Pro residues using bradykinin (BK), a partially unstructured nonapeptide hormone, as a model system.

Liquid-Vapor Coexistence and Spontaneous Evaporation at Atmospheric Pressure of Common Rigid Three-Point Water Models in Molecular Simulations.

Molecular dynamics (MD) simulations are widely used to investigate molecular systems at atomic resolution including biomolecular structures, drug-receptor interactions, and novel materials. Frequently, MD simulations are performed in an aqueous solution with explicit models of water molecules. Commonly, such models are parameterized to reproduce the liquid phase of water under ambient conditions.

Pronucleotide Probes Reveal a Diverging Specificity for AMPylation vs UMPylation of Human and Bacterial Nucleotide Transferases.

AMPylation is a post-translational modification utilized by human and bacterial cells to modulate the activity and function of specific proteins. Major AMPylators such as human FICD and bacterial VopS have been studied extensively for their substrate and target scope . Recently, an AMP pronucleotide probe also facilitated the analysis of AMPylation in living cells.

A Pd-labile fluoroquinolone prodrug efficiently prevents biofilm formation on coated surfaces.

Surface-adhered bacteria on implants represent a major challenge for antibiotic treatment. We introduce hydrogel-coated surfaces loaded with tailored Pd-nanosheets which catalyze the release of antibiotics from inactive prodrugs. Masked and antibiotically inactive fluoroquinolone analogs were efficiently activated at the surface and prevented the formation of biofilms.

Monitoring host-pathogen interactions using chemical proteomics.

With the rapid emergence and the dissemination of microbial resistance to conventional chemotherapy, the shortage of novel antimicrobial drugs has raised a global health threat. As molecular interactions between microbial pathogens and their mammalian hosts are crucial to establish virulence, pathogenicity, and infectivity, a detailed understanding of these interactions has the potential to reveal novel therapeutic targets and treatment strategies. Bidirectional molecular communication between microbes and eukaryotes is essential for both pathogenic and commensal organisms to colonise their host.

Lubricity, wear prevention, and anti-biofouling properties of macromolecular coatings for endotracheal tubes.

Macromolecular coatings can improve the surface properties of many medical devices by enhancing their wetting behavior, tribological performance, and anti-biofouling properties - and covalent coatings produced from mucin glycoproteins have been shown to be very powerful in all those aspects. However, obtaining highly functional mucin glycoproteins is, at the moment, still a time-consuming process, which renders mucins rather expensive compared to other biomacromolecules. Here, we study a set of commercially available macromolecules that have the potential of substituting mucins in coatings for endotracheal tubes (ETTs).

Design of cyclic peptides as novel inhibitors of ICOS/ICOSL interaction.

Compared to small molecules and antibodies, cyclic peptides exhibit unique biochemical and therapeutic attributes in the realm of pharmaceutical applications. The interaction between the inducible costimulator (ICOS) and its ligand (ICOSL) plays a key role in T-cell differentiation and activation. ICOS/ICOSL inhibition results in a reduction in the promotion of immunosuppressive regulatory T cells (Tregs) in both hematologic malignancies and solid tumors.

How Modulator Binding at the Amyloidβ-γ-Secretase Interface Enhances Substrate Binding and Attenuates Membrane Distortion.

Inhibition of γ-secretase, an intramembrane protease, to reduce secretion of Amyloid-β (Aβ) peptides has been considered for treating Alzheimer's disease. However, γ-secretase inhibitors suffer from severe side effects. As an alternative, γ-secretase modulators (GSM) reduce the generation of toxic peptides by enhancing the cleavage processivity without diminishing the enzyme activity.

Structure of Staphylococcus aureus ClpP Bound to the Covalent Active-Site Inhibitor Cystargolide A.

The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Herein, we describe the potent cystargolides as the first natural β-lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target.

The DNA-binding induced (de)AMPylation activity of a Coxiella burnetii Fic enzyme targets Histone H3.

The intracellular bacterial pathogen Coxiella burnetii evades the host response by secreting effector proteins that aid in establishing a replication-friendly niche. Bacterial filamentation induced by cyclic AMP (Fic) enzymes can act as effectors by covalently modifying target proteins with the posttranslational AMPylation by transferring adenosine monophosphate (AMP) from adenosine triphosphate (ATP) to a hydroxyl-containing side chain. Here we identify the gene product of C.

Assembly-dependent Structure Formation Shapes Human Interleukin-23 versus Interleukin-12 Secretion.

Interleukin 12 (IL-12) family cytokines connect the innate and adaptive branches of the immune system and regulate immune responses. A unique characteristic of this family is that each member is anα:βheterodimer. For human αsubunits it has been shown that they depend on theirβsubunit for structure formation and secretion from cells.

Efficient and accurate calculation of proline cis/trans isomerization free energies from Hamiltonian replica exchange molecular dynamics simulations.

Proline cis/trans isomerization plays an important role in many biological processes but occurs on time scales not accessible to brute-force molecular dynamics (MD) simulations. We have designed a new Hamiltonian replica exchange scheme, ω-bias potential replica exchange molecular dynamics (ωBP-REMD), to efficiently and accurately calculate proline cis/trans isomerization free energies. ωBP-REMD is applied to various proline-containing tripeptides and a biologically important proline residue in the N2-domain of the gene-3-protein of phage fd in the wildtype and mutant variants of the protein.

Practical guidelines for the use of gradient boosting for molecular property prediction.

Decision tree ensembles are among the most robust, high-performing and computationally efficient machine learning approaches for quantitative structure-activity relationship (QSAR) modeling. Among them, gradient boosting has recently garnered particular attention, for its performance in data science competitions, virtual screening campaigns, and bioactivity prediction. However, different variants of gradient boosting exist, the most popular being XGBoost, LightGBM and CatBoost.

Modeling of the human interleukin 12:receptor complex allows to engineer attenuated cytokine variants.

Interleukin 12 (IL-12) plays major roles in immune defense against intracellular pathogens. By activating T cells and increasing antigen presentation, it is also a very potent anti-tumor molecule. Strong immune activation and systemic toxicity, however, so far limit its potential therapeutic use.