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The HADDOCK2.4 web server for integrative modeling of biomolecular complexes

Nature Protocols volume 19, pages 3219–3241 (2024)Cite this article

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Abstract

Interactions between macromolecules, such as proteins and nucleic acids, are essential for cellular functions. Experimental methods can fail to provide all the information required to fully model biomolecular complexes at atomic resolution, particularly for large and heterogeneous assemblies. Integrative computational approaches have, therefore, gained popularity, complementing traditional experimental methods in structural biology. Here, we introduce HADDOCK2.4, an integrative modeling platform, and its updated web interface (https://wenmr.science.uu.nl/haddock2.4). The platform seamlessly integrates diverse experimental and theoretical data to generate high-quality models of macromolecular complexes. The user-friendly web server offers automated parameter settings, access to distributed computing resources, and pre- and post-processing steps that enhance the user experience. To present the web server’s various interfaces and features, we demonstrate two different applications: (i) we predict the structure of an antibody–antigen complex by using NMR data for the antigen and knowledge of the hypervariable loops for the antibody, and (ii) we perform coarse-grained modeling of PRC1 with a nucleosome particle guided by mutagenesis and functional data. The described protocols require some basic familiarity with molecular modeling and the Linux command shell. This new version of our widely used HADDOCK web server allows structural biologists and non-experts to explore intricate macromolecular assemblies encompassing various molecule types.

Key points

  • HADDOCK is an integrative modeling approach that can combine experimental and predicted information to guide the structure prediction of biomolecular complexes, including protein–protein, protein–ligand, protein–oligosaccharide and protein–nucleic acid complexes, starting from the individual structures of their components.

  • HADDOCK uses ambiguous interaction restraints to drive the docking process and supports various experimental data, including mutagenesis, NMR and cryo-EM data.

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Fig. 1: Overall structure of the HADDOCK2.4 web server.
Fig. 2: HADDOCK server statistics for the period January 2020 to June 2023.
Fig. 3: Overview of the HADDOCK2.4 result page.
Fig. 4: Online visualization of active/passive residues.

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Data availability

All data used in the procedures are available at a dedicated GitHub repository54: https://github.com/haddocking/haddock24-protocol.

Code availability

pdb-tools is available at https://github.com/haddocking/pdb-tools (Apache 2.0)55, and the HADDOCK2.4 web service application (used in the described protocols) is available at https://wenmr.science.uu.nl/haddock2.4.

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Acknowledgements

The authors acknowledge financial support from the European Union Horizon 2020, projects BioExcel (675728, 823830), from the EuroHPC Joint Undertaking and Sweden, Netherlands, Germany, Spain, Finland and Norway (101093290) and from the Dutch Foundation for Scientific Research (NWO) (TOP-PUNT grant 718.015.001). The FP7 WeNMR (261572), H2020 West-Life (675858), EOSC-hub (777536) and EGI-ACE (101017567) European e-Infrastructure projects are acknowledged for the use of the EGI infrastructure with the dedicated support of CESNET-MCC, INFN-LNL-2, NCG-INGRID-PT, TW-NCHC, CESGA, IFCA-LCG2, UA-BITP, TR-FC1-ULAKBIM, CSTCLOUD-EGI, IN2P3-CPPM, CIRMMP, SURFsara and NIKHEF and the additional support of the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, Taiwan and the US Open Science Grid.

Author information

Author notes

  1. Mikael E. Trellet

    Present address: Fluigent, Le Kremlin-Bicêtre, France

  2. Brian Jiménez-García

    Present address: Zymvol Biomodeling SL, Barcelona, Spain

  3. Jörg J. Schaarschmidt

    Present address: Karlsruhe Institute of Technology (KIT), Institute of Nanotechnology, Eggenstein-Leopoldshafen, Germany

  4. Panagiotis I. Koukos

    Present address: Biomedical Research Foundation, Academy of Athens, Athens, Greece

  5. João P. G. L. M. Rodrigues & Gydo C. P. van Zundert

    Present address: Schrödinger Inc., New York, NY, USA

  6. Ezgi Karaca

    Present address: Izmir Biomedicine and Genome Center, Izimir, Turkey

  7. Jorge Roel-Touris

    Present address: Protein Design and Modeling Lab, Department of Structural Biology, Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain

  8. Zuzana Jandová

    Present address: Boehringer Ingelheim International GmbH, Vienna, Austria

  9. Adrien S. J. Melquiond

    Present address: Utrecht Medical Center, Utrecht, the Netherlands

Authors and Affiliations

  1. Computational Structural Biology Group, Bijvoet Centre for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    Rodrigo V. Honorato, Mikael E. Trellet, Brian Jiménez-García, Jörg J. Schaarschmidt, Marco Giulini, Victor Reys, Panagiotis I. Koukos, João P. G. L. M. Rodrigues, Ezgi Karaca, Gydo C. P. van Zundert, Jorge Roel-Touris, Charlotte W. van Noort, Zuzana Jandová, Adrien S. J. Melquiond & Alexandre M. J. J. Bonvin

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  1. Rodrigo V. Honorato
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Contributions

A.M.J.J.B. supervised the project. All authors contributed to the development of HADDOCK2.4 and the various protocols and types of molecules supported. R.V.H., M.E.T, B.J.-G., J.J.S. and P.I.K. contributed to the development of the web interface. A.M.J.J.B. and R.V.H. wrote the manuscript. All authors contributed to the manuscript editing and checking.

Corresponding author

Correspondence to Alexandre M. J. J. Bonvin.

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The authors declare no competing interests.

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Nature Protocols thanks George Chiduza and Cedric Leyrat for their contribution to the peer review of this work.

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Related links

Key references using this protocol

de Vries, S. J. et al. Nat. Protoc. 5, 883–897 (2010): https://doi.org/10.1038/nprot.2010.32

Honorato, R. V. et al. Front. Mol. Biosci. 6, 102 (2019): https://doi.org/10.3389/fmolb.2019.00102

Ambrosetti, F. et al. Structure 28, 119–129.e2 (2020): https://doi.org/10.1016/j.str.2019.10.011

Extended data

Extended Data Fig. 1

Screenshots showing Steps 7–9 of Procedure 1.

Extended Data Fig. 2

Screenshots showing Steps 10–11 of Procedure 1.

Extended Data Fig. 3

Screenshots showing Steps 12–13 of Procedure 1.

Extended Data Fig. 4

Screenshots showing Steps 14–15 of Procedure 1.

Extended Data Fig. 5

Screenshots showing Step 20 of Procedure 1.

Supplementary Information

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Honorato, R.V., Trellet, M.E., Jiménez-García, B. et al. The HADDOCK2.4 web server for integrative modeling of biomolecular complexes. Nat Protoc 19, 3219–3241 (2024). https://doi.org/10.1038/s41596-024-01011-0

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