User-centric design of a 3D search interface for protein-ligand complexes.

In this work, we present the frontend of GeoMine and showcase its application, focusing on the new features of its latest version. GeoMine is a search engine for ligand-bound and predicted empty binding sites in the Protein Data Bank. In addition to its basic text-based search functionalities, GeoMine offers a geometric query type for searching binding sites with a specific relative spatial arrangement of chemical features such as heavy atoms and intermolecular interactions. In contrast to a text search that requires simple and easy-to-formulate user input, a 3D input is more complex, and its specification can be challenging for users. GeoMine's new version aims to address this issue from the graphical user interface perspective by introducing an additional visualization concept and a new query template type. In its latest version, GeoMine extends its query-building capabilities primarily through input formulation in 2D. The 2D editor is fully synchronized with GeoMine's 3D editor and provides the same functionality. It enables template-free query generation and template-based query selection directly in 2D pose diagrams. In addition, the query generation with the 3D editor now supports predicted empty binding sites for AlphaFold structures as query templates. GeoMine is freely accessible on the ProteinsPlus web server ( https://proteins.plus ).

PoseEdit: enhanced ligand binding mode communication by interactive 2D diagrams.

In this article, we present PoseEdit, a new, interactive frontend of the popular pose visualization tool PoseView. PoseEdit automatically produces high-quality 2D diagrams of intermolecular interactions in 3D binding sites calculated from ligands in complex with protein, DNA, and RNA. The PoseView diagrams have been improved in several aspects, most notably in their interactivity. Thanks to the easy-to-use 2D editor of PoseEdit, the diagrams are extensively editable and extendible by the user, can be merged with other diagrams, and even be created from scratch. A large variety of graphical objects in the diagram can be moved, rotated, selected and highlighted, mirrored, removed, or even newly added. Furthermore, PoseEdit enables a synchronized 2D-3D view of macromolecule-ligand complexes simplifying the analysis of structural features and interactions. The representation of individual diagram objects regarding their visualized chemical properties, like stereochemistry, and general graphical styles, like the color of interactions, can additionally be edited. The primary objective of PoseEdit is to support scientists with an enhanced way to communicate ligand binding mode information through graphical 2D representations optimized with the scientist's input in accordance with objective criteria and individual needs. PoseEdit is freely available on the ProteinsPlus web server ( https://proteins.plus ).

ProteinsPlus: a comprehensive collection of web-based molecular modeling tools.

Upon the ever-increasing number of publicly available experimentally determined and predicted protein and nucleic acid structures, the demand for easy-to-use tools to investigate these structural models is higher than ever before. The ProteinsPlus web server (https://proteins.plus) comprises a growing collection of molecular modeling tools focusing on protein-ligand interactions. It enables quick access to structural investigations ranging from structure analytics and search methods to molecular docking. It is by now well-established in the community and constantly extended. The server gives easy access not only to experts but also to students and occasional users from the field of life sciences. Here, we describe its recently added new features and tools, beyond them a novel method for on-the-fly molecular docking and a search method for single-residue substitutions in local regions of a protein structure throughout the whole Protein Data Bank. Finally, we provide a glimpse into new avenues for the annotation of AlphaFold structures which are directly accessible via a RESTful service on the ProteinsPlus web server.

Searching Geometric Patterns in Protein Binding Sites and Their Application to Data Mining in Protein Kinase Structures.

The ever-growing number of protein-ligand complex structures can give fundamental insights into protein functions and protein-ligand interactions, especially in the field of protein kinase research. The number of tools to mine this data for individually defined structural motifs is restricted due to the challenging task of developing efficient index structures for 3D data in relational databases. Herein we present GeoMine, a database system with web front-end mining of more than 900 000 binding sites. It enables database searches for geometric (interaction) patterns in protein-ligand interfaces by, for example, textual, numerical, substructure, similarity, and 3D searches. GeoMine processes reasonably selective user-defined queries within minutes. We demonstrate its usability for advancing protein kinase research with a special emphasis on unusual interactions, their use in designing selective kinase inhibitors, and the analysis of reactive cysteine residues that are amenable to covalent kinase inhibitors. GeoMine is freely available as part of our modeling support server at https://proteins.plus.

GeoMine: interactive pattern mining of protein-ligand interfaces in the Protein Data Bank.

SUMMARY: The searching of user-defined 3D queries in molecular interfaces is a computationally challenging problem that is not satisfactorily solved so far. Most of the few existing tools focused on that purpose are desktop based and not openly available. Besides that, they show a lack of query versatility, search efficiency and user-friendliness. We address this issue with GeoMine, a publicly available web application that provides textual, numerical and geometrical search functionality for protein-ligand binding sites derived from structural data contained in the Protein Data Bank (PDB). The query generation is supported by a 3D representation of a start structure that provides interactively selectable elements like atoms, bonds and interactions. GeoMine gives full control over geometric variability in the query while performing a deterministic, precise search. Reasonably selective queries are processed on the entire set of protein-ligand complexes in the PDB within a few minutes. GeoMine offers an interactive and iterative search process of successive result analyses and query adaptations. From the numerous potential applications, we picked two from the field of side-effect analyze showcasing the usefulness of GeoMine. AVAILABILITY AND IMPLEMENTATION: GeoMine is part of the ProteinsPlus web application suite and freely available at https://proteins.plus. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

ProteinsPlus: interactive analysis of protein-ligand binding interfaces.

Due to the increasing amount of publicly available protein structures searching, enriching and investigating these data still poses a challenging task. The ProteinsPlus web service (https://proteins.plus) offers a broad range of tools addressing these challenges. The web interface to the tool collection focusing on protein-ligand interactions has been geared towards easy and intuitive access to a large variety of functionality for life scientists. Since our last publication, the ProteinsPlus web service has been extended by additional services as well as it has undergone substantial infrastructural improvements. A keyword search functionality was added on the start page of ProteinsPlus enabling users to work on structures without knowing their PDB code. The tool collection has been augmented by three tools: StructureProfiler validates ligands and active sites using selection criteria of well-established protein-ligand benchmark data sets, WarPP places water molecules in the ligand binding sites of a protein, and METALizer calculates, predicts and scores coordination geometries of metal ions based on surrounding complex atoms. Additionally, all tools provided by ProteinsPlus are available through a REST service enabling the automated integration in structure processing and modeling pipelines.

Analysis of the Expression and Single-Nucleotide Variant Frequencies of the Butyrophilin-like 2 Gene in Patients With Uveal Melanoma.

IMPORTANCE: Chromosome 6p amplification is associated with more benign behavior for uveal melanomas (UMs) with an otherwise high risk of metastasis conferred by chromosome 3 monosomy. Chromosome 6p contains several members of the B7 family of immune regulator genes, including butyrophilin-like 2 (BTNL2; OMIM, 606000), which is associated with prostate cancer risk and autoimmune diseases. OBJECTIVE: To investigate the expression and variant allele frequencies of BTNL2, a candidate gene for chromosome 6 amplification, in patients with UM. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, we analyzed the expression of BTNL2 in UM cell lines and human macrophages in patients with UM. Variants of BTNL2 were analyzed using probes for polymerase chain reaction and high-resolution melting. The association of missense variants rs28362679 and rs41441651 with tumor risk was analyzed in 209 patients with UM and 116 matched control patients as well as 12 UM and 64 other tumor cell lines. Genes that were differentially expressed in M1- and M2-polarized macrophages were identified by microarray analysis of 111 patients with UM, and the association of the expression of these genes with disease-free survival was analyzed by Cox regression analysis. Data were collected from September 2013 to November 2015. MAIN OUTCOMES AND MEASURES: Butyrophilin-like 2 single-nucleotide variants were associated with UM risk; M1 and M2 macrophage-specific gene expression was associated with disease-free survival. RESULTS: We genotyped a total of 325 patients. Of the 209 patients with UM, 124 (59.3%) were male, 114 (54.5%) were Italian, and 95 (45.5%) were German; the mean (range) age was 65 (27-94) years. Of the 116 Italian control patients, 67 (57.8%) were female, and the mean (range) age was 39 (21-88) years. Butyrophilin-like 2 is expressed in patients with UM and macrophages. The frequency of the rs28362679 variant was higher in patients with UM (16 of 209 [7.7%]; 95% CI, 4.7-12.2) than frequencies from European Variation Archive and Exome Aggregation Consortium data (2134 of 118 564 [1.8%]; 95% CI, 1.7-1.9) and Exome Sequencing Project data (100 of 4540 [2.2%]; 95% CI, 1.8-2.7) but were not higher compared with Italian control patients (10 of 116 [8.6%]; 95% CI, 4.6-15.4). The rs41441651 variant was present in 5 patients with UM (2.4%; 95% CI, 0.9-5.7), 2 Italian control patients (1.7%; 95% CI, 0.1-6.5), 2846 patients from European Variation Archive and Exome Aggregation Consortium data (2.4%; 95% CI, 2.3-2.5), and 23 patients from Exome Sequencing Project data (0.5%; 95% CI, 0.3-0.8). Human UM cells express M1 and M2 macrophage-specific genes, whose expression is associated with disease-free survival. CONCLUSIONS AND RELEVANCE: Butyrophilin-like 2, expressed at various levels by UM cells and macrophages, might interfere with the immune control of the tumor. Butyrophilin-like 2 variants showed highly variable frequencies among ethnically related cohorts. There was no enrichment of BTNL2 variants in patients with UM compared with control patients.