The available protein structure data are rapidly increasing. Within these structures, numerous local structural sites depict the details characterizing structure and function. However, searching and analyzing these sites extensively and at scale poses a challenge. We present a new method to search local sites in protein structure databases using residue-defined local 3D micro-environments. We implemented the method in a new tool called MicroMiner and demonstrate the capabilities of residue micro-environment search on the example of structural mutation analysis. Usually, experimental structures for both the wild-type and the mutant are unavailable for comparison. With MicroMiner, we extracted $>255 \times 10^{6}$ amino acid pairs in protein structures from the PDB, exemplifying single mutations' local structural changes for single chains and $>45 \times 10^{6}$ pairs for protein-protein interfaces. We further annotate existing data sets of experimentally measured mutation effects, like $\Delta \Delta G$ measurements, with the extracted structure pairs to combine the mutation effect measurement with the structural change upon mutation. In addition, we show how MicroMiner can bridge the gap between mutation analysis and structure-based drug design tools. MicroMiner is available as a command line tool and interactively on the https://proteins.plus/ webserver.

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.

MOTIVATION: Three-dimensional protein structures are important starting points for elucidating protein function and applications like drug design. Computational methods in this area rely on high quality validation datasets which are usually manually assembled. Due to the increase in published structures as well as the increasing demand for specially tailored validation datasets, automatic procedures should be adopted. RESULTS: StructureProfiler is a new tool for automatic, objective and customizable profiling of X-ray protein structures based on the most frequently applied selection criteria currently in use to assemble benchmark datasets. As examples, four dataset configurations (Astex, Iridium, Platinum, combined), all results of the combined tests and the list of all PDB Ids passing the combined criteria set are attached in the Supplementary Material. AVAILABILITY AND IMPLEMENTATION: StructureProfiler is available as part of the ProteinsPlus web service http://proteins.plus and as standalone tool in the NAOMI ChemBio Suite. Dataset updates together with the tool can be found on http://www.zbh.uni-hamburg.de/structureprofiler. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Many drug discovery projects fail because the underlying target is finally found to be undruggable. Progress in structure elucidation of proteins now opens up a route to automatic structure-based target assessment. DoGSiteScorer is a newly developed automatic tool combining pocket prediction, characterization and druggability estimation and is now available through a web server. AVAILABILITY: The DoGSiteScorer web server is freely available for academic use at http://dogsite.zbh.uni-hamburg.de CONTACT: [email protected].

MOTIVATION: In this paper a new algorithmic approach is presented, which automatically generates structure diagrams of molecular complexes. A complex diagram contains the ligand, the amino acids of the protein interacting with the ligand and the hydrophilic interactions schematized as dashed lines between the corresponding atoms. The algorithm is based on a combinatorial optimization strategy which solves parts of the layout problem non-heuristically. The depicted molecules are represented as structure diagrams according to the chemical nomenclature. Due to the frequent usage of complex diagrams in the scientific literature as well as in text books dealing with structural biology, biochemistry and medicinal chemistry, the new algorithm is a key element for computer applications in these areas. RESULTS: The method was implemented in the new software tool PoseView. It was tested on a representative dataset containing 305 protein-ligand complexes in total from the Brookhaven Protein Data Bank. PoseView was able to find collision-free layouts for more than three quarters of all complexes. In the following the layout generation algorithm is presented and, additional to the statistical results, representative test cases demonstrating the challenges of the layout generation will be discussed. AVAILABILITY: The method is available as a webservice at http://www.zbh.uni-hamburg.de/poseview.

SUMMARY: The Helmholtz Network for Bioinformatics (HNB) is a joint venture of eleven German bioinformatics research groups that offers convenient access to numerous bioinformatics resources through a single web portal. The 'Guided Solution Finder' which is available through the HNB portal helps users to locate the appropriate resources to answer their queries by employing a detailed, tree-like questionnaire. Furthermore, automated complex tool cascades ('tasks'), involving resources located on different servers, have been implemented, allowing users to perform comprehensive data analyses without the requirement of further manual intervention for data transfer and re-formatting. Currently, automated cascades for the analysis of regulatory DNA segments as well as for the prediction of protein functional properties are provided. AVAILABILITY: The HNB portal is available at http://www.hnbioinfo.de

MOTIVATION: Matching of chemical interacting groups is a common concept for docking and fragment placement algorithms in computer-aided drug design. These algorithms have been proven to be reliable and fast if at least a certain number of hydrogen bonds or salt bridges occur. However, the algorithms typically run into problems if hydrophobic fragments or ligands should be placed. In order to dock hydrophobic fragments without significant loss of computational efficiency, we have extended the interaction model and placement algorithms in our docking tool FlexX. The concept of multi-level interactions is introduced into the algorithms for automatic selection and placement of base fragments. RESULTS: With the multi-level interaction model and the corresponding algorithmic extensions, we were able to improve the overall performance of FlexX significantly. We tested the approach with a set of 200 protein-ligand complexes taken from the Brookhaven Protein Data Bank (PDB). The number of test cases which can be docked within 1.5 A RMSD from the crystal structure can be increased from 58 to 64%. The performance gain is paid for by an increase in computation time from 73 to 91 s on average per protein-ligand complex. AVAILABILITY: The FlexX molecular docking software is available for UNIX platforms IRIX, Solaris and Linux. See http://cartan.gmd.de/FlexX for additional information.