About ProteinsPlus

The aim of ProteinsPlus is to support life scientists in working with protein structures ^1,2,3. Protein structures are the key for an understanding of function. They are an important resource in many biotechnological application areas from pharmaceutical research to biocatalysis. ProteinsPlus has its focus on protein-ligand interactions. The server provides support for the initial steps when dealing with protein structures, namely structure search, quality assessment, and preprocessing. Furthermore, advanced options, such as protein pocket detection, ensemble generation or prediction of metal coordinations are supported. All tools are developed in the Computational Molecular Design Group (AMD) headed by Matthias Rarey. Currently, ProteinsPlus allows you to:

• Measure and visualize electron density support for individual atoms and structural units (EDIA)⁴

• Screening of structures based on selection criteria (StructureProfiler)⁵

• Visualize structures and create 2D pose depictions (PoseView)⁶

• Predict protonation and tautomerization, place hydrogen atoms (Protoss)^7,8

• Generate SMILES notations for small molecules in PDB files^9,10

• Predict binding sites and estimate their druggability (DoGSiteScorer)¹¹

• Search for alternative binding site models and conformations and generate aligned protein structure ensembles (SIENA)^12,13

• Classify the interaction type of protein-protein complexes (HyPPI)

• Prediction of coordinates of metals in metalloproteins (METALizer)

• Placement of water molecules in the active site (WarPP)¹⁴

• Find structural data of the PDB to activity values stored in the ChEMBL database (ActivityFinder - alpha release)

• Textual, numerical, and chemical 3D searching in the PDB (GeoMine)^15,16,17

• Fully automated protein-ligand docking (JAMDA)¹⁸

• Search mutations in protein structure databases like the PDB (MicroMiner)

• Predict binding sites and estimate their druggability (DoGSite3)¹⁹

• Visualize interactive 2D ligand interaction diagrams (PoseEdit)²⁰

• Calculate solvent channels and their corresponding bottleneck radii (LifeSoaks)²¹

Several of the underlying tools are components of professional molecular modeling software provided by BioSolveIT GmbH. Some tools are available as part of the NAOMI Chembio Suite for stand-alone use in academic and commercial environments from us.

The development of the ProteinsPlus web service is supported by the BMBF as part of de.NBI – German Network for Bioinformatics Infrastructure. Its use is free for academic and commercial purposes – we thank you for citing the ProteinsPlus and the computational methods behind it. You find the corresponding references below and in the short description of each tool.

ProteinsPlus is a common framework to make computational tools for structure- based molecular design developed in the AMD research group of Prof. Matthias Rarey available on the web. For more information on scientific literature, software availability, and projects we refer to our group homepage and to the web page of our software development partner BioSolveIT. Everybody from the AMD group provided components in use behind ProteinsPlus. The ProteinsPlus web server was originally developed by Rainer Fährrolfes. Many thanks to Ruben Steinegger who developed the keyword search functionality on top of the PDB RESTful service (Bachelor thesis at the Technische Hochschule Mittelhessen (THM)) as well as to Konrad Diedrich and Lennart Weihs for integrating the REST Api for the ProteinsPlus web service.

The ProteinsPlus server and all its attached components are provided as is. Any warranties, including, but not limited to correctness, fitness for a particular purpose, data safety are disclaimed. In no event, the University of Hamburg shall be liable for any direct or indirect damages.

To justify funding for our web services, we are obliged to collect statistical information about their usage. The package Matomo is applied to gather the following user information in an anonymous form:

In case you want to use our tools without tracking of any kind, we encourage you to install software components locally. Software licenses are provided free of charge for academic use (for further information see http://software.zbh.uni-hamburg.de).

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The server uses the following technology:

• Ruby On Rails: rubyonrails.org
• NGL Viewer: github.com/arose/ngl
• Chart.js: github.com/chartjs/Chart.js
• Moment.js: github.com/moment/moment
• DataTables: datatables.net
• Bootstrap: getbootstrap.com
• DelayedJob: github.com/collectiveidea/delayed_job_active_record
• Paperclip: github.com/thoughtbot/paperclip
• D3: Data-Driven Documents: d3js.org
• Matomo: matomo.org
• The RCSB PDB RESTful Web Service interface: rcsb.org
• jQuery UI Slider Pips: github.com/simeydotme/jQuery-ui-Slider-Pips
• SmilesDrawer: github.com/reymond-group/smilesDrawer

We thank all developers for generously providing this software.

References

ProteinsPlus should be referenced with the URL https://proteins.plus and the following citation:

Schöning-Stierand, K.; Diedrich, K.; Ehrt, C.; Flachsenberg, F.; Graef, J.; Sieg, J.; Penner, P.; Poppinga, M.; Ungethüm, A.; Rarey, M. (2022). ProteinsPlus: a comprehensive collection of web-based molecular modeling tools. Nucleic Acids Research, 50:W611-W615. Schöning-Stierand, K.; Diedrich, K.; Fährrolfes, R.; Flachsenberg, F.; Meyder, A.; Nittinger, E.; Steinegger, R.; Rarey, M. (2020). ProteinsPlus: interactive analysis of protein–ligand binding interfaces. Nucleic Acids Research, 48:W48-W53. Fährrolfes, R.; Bietz, S.; Flachsenberg, F.; Meyder, A.; Nittinger, E.; Otto, T.; Volkamer, A.; Rarey, M. (2017). ProteinsPlus: a web portal for structure analysis of macromolecules. Nucleic Acids Research, 45:W337-W343.

Results of individual tools should be referenced with the appropriate citation from the following list:

Meyder, A.; Nittinger, E.; Lange, G.; Klein, R.; Rarey, M. (2017). Estimating Electron Density Support for Individual Atoms and Molecular Fragments in X-ray Structures. Journal of Chemical Information and Modeling, 57(10): 2437–2447. Meyder, A.; Kampen, S.; Sieg, J.; Fährrolfes, R.; Friedrich, N.-O.; Flachsenberg, F.; Rarey, M. (2018). StructureProfiler: An all-in-one Tool for 3D Protein Structure Profiling. Bioinformatics, 35(5): 874-876. Stierand, K.; Maass, P. C.; Rarey, M. (2010). Drawing the PDB - Protein-Ligand Complexes in two Dimensions. Medicinal Chemistry Letters, 1 (9) 540-545. Lippert, T., Rarey, M. (2009). Fast automated placement of polar hydrogen atoms in protein-ligand complexes. Journal of Cheminformatics, 1:13. Bietz, S., Urbaczek, S., Schulz, B., Rarey, M. (2014). Protoss: a holistic approach to predict tautomers and protonation states in protein-ligand complexes. Journal of Cheminformatics, 6:12. Hilbig, M.; Urbaczek, S.; Groth, I.; Heuser, S.; Rarey, M. (2013). MONA–Interactive manipulation of molecule collections. Journal of cheminformatics, 5(1), 38. Hilbig, M.; Rarey, M. (2015). MONA 2: a light cheminformatics platform for interactive compound library processing. Journal of Chemical Information and Modeling. 55 (10), 2071-2078. Volkamer, A.; Kuhn, D.; Grombacher, D.; Rippmann, F.; Rarey, M.. Combining global and local measures for structure-based druggability predictions. J. Chem. Inf. Model. 2012,52,360-372. Bietz, S.; Rarey, M. (2016). SIENA: Efficient Compilation of Selective Protein Binding Site Ensembles. Journal of Chemical Information and Modeling, 56 (1), pp 248–259. Bietz, S.; Rarey, M. (2015). ASCONA: Rapid Detection and Alignment of Protein Binding Site Conformations. Journal of Chemical Information and Modeling 55 (8), 1747-1756. Nittinger, E.; Flachsenberg, F.; Bietz, S.; Lange, G.; Klein, R.; Rarey, M.(2018). Placement of Water Molecules in Protein Structures: From Large-Scale Evalutations to Single-Case Examples. Journal of Chemical Information and Modeling, 58 (8), pp 1625-1637. Inhester, T.; Bietz, S.; Hilbig, M.; Schmidt, R.; Rarey, M. (2017). Index-Based Searching of Interaction Patterns in Large Collections of Protein-Ligand Interfaces. Journal of Chemical Information and Modeling, 57, 2, 148-158. Diedrich, K.; Graef, J.; Schöning-Stierand, K.; Rarey, M. (2020). GeoMine: interactive pattern mining of protein-ligand interfaces in the Protein Data Bank. Bioinformatics, Volume 37, Issue 3, 1 February 2021, 424-425. Graef, J.; Ehrt, C.; Diedrich, K.; Poppinga, M.; Ritter, N.; Rarey, M. (2021). Searching Geometric Patterns in Protein Binding Sites and Their Application to Data Mining in Protein Kinase Structures. Journal of Chemical Information and Modeling, doi: https://doi.org/10.1021/acs.jmedchem.1c01046. Flachsenberg, F.; Meyder, A.; Penner, P.; Sommer, K.; Rarey, M. (2021). A Consistent Scheme for Gradient-Based Optimization of Protein-Ligand Poses. J. Chem. Inf. Model., doi: 10.1021/acs.jcim.0c01095. Graef, J.; Ehrt, C.; Rarey, M. (2023). Binding Site Detection Remastered: Enabling Fast, Robust, and Reliable Binding Site Detection and Descriptor Calculation with DoGSite3. J. Chem. Inf. Model., 63, 10, 3128–3137, doi: 10.1021/acs.jcim.3c00336 Diedrich, K.; Krause, B.; Berg, O.; Rarey, M. (2023). PoseEdit: enhanced ligand binding mode communication by interactive 2D diagrams. J Comput Aided Mol Des 2023, doi: doi.org/10.1007/s10822-023-00522-4 Pletzer-Zelgert, J.; Ehrt, C.; Fender, I.; Griewel, A.; Flachsenberg, F.; Klebe, G.; Rarey, M. (2023). LifeSoaks: a tool for analyzing solvent channels in protein crystals and obstacles for soaking experiments. Acta Cryst. 2023, doi: doi.org/10.1107/S205979832300582X

We are happy to receive feedback and comments, please contact us via e-mail at pplus(at)zbh.uni-hamburg.de.

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