A worldwide e-Infrastructure for NMR and structural biology

Getting started with HADDOCK

HADDOCK is an acronym for High Ambiguity Driven DOCKing and is a program to predict structures of biomolecular complexes from individual components. As the full name indicates, this approach in docking of biomolecules distinguishes itself from other methods by using external information to guide the docking process. Such information can be empirical, theoretical or both, pertaining to the residues or atoms involved in the binding interface. From this information ambiguous restraints are derived that are used to drive the docking. HADDOCK is particularly useful in predicting complexes from known experimental structures of the partners using NMR data, such as chemical shift perturbations and residual dipolar couplings (RDCs). Chemical shift perturbations and RDCs can be obtained relatively easily and also for macromolecules of increasing size, making the large applicability of HADDOCK as a tool for cutting edge Structural Biology apparent.  HADDOCK has proven its value within the CAPRI (Critical Assessment of PRediction of Interactions) experiment, a blind evaluation of the performance of current docking methods. 

The docking process starts with random placement of the individual components with a given separation and random orientations. Subsequently, a large number of complex structures, typically in the order of thousands, is generated by rigid-body docking, driven by the ambiguous restraints. From these a number of structures, typically several hundred, are selected for further refinement, using a scoring function. These structures are first subjected to a further cycle of simulated annealing, introducing flexibility to allow optimization of contacts. After this, a final cycle of refinement follows, in which the complex is solvated. The results are then scored, analyzed and returned to the user. The structure calculations are the CPU intensive part of the process and involve a combination of energy minimization and MD (in torsion angle or Cartesian space) simulations.

HADDOCK offers almost full control of the many parameters involved in the docking process. To offer the full functionality of HADDOCK through a web portal thus requires putting forth a complicated form, contrasting with the objective of having a simple interface. To avoid compromises regarding user friendliness and functionality, two innovations were introduced in the design of the portal. First of all, the portal is divided in four interfaces, corresponding to different levels of control and user experience:

  • The Easy Interface requires no more than providing the two components of a complex and the residues of each that are involved in the interaction.
  • The Expert Interface allows the user to provide his own customized restraints to be included in the docking process and to specify certain aspects of the sampling and analysis. In addition, using this interface the user can set protonation states of histidine residues, and define regions of the interacting molecules to be kept flexible during the docking. This allows a certain degree of conformational change to take place during docking.
  • The Guru Interface offers almost full control of parameters, allowing e.g. specification of symmetry and relaxation anisotropy restraints and RDCs as well as of parameters pertaining to the energy, the scoring and the analysis of results.
  • Finally, for complete control a File Upload Interface is available, where a HADDOCK run parameter file can be provided. This is particularly useful for those who have their own standard protocol or who want to replicate a previous run with minor modifications. This option also offers a simple way to build pipelines from other applications.

The Expert and Guru interface offer control of the docking process at the expense of making the forms to be filled in more complex. Thus, to facilitate the user’s task and keep the forms manageable, foldable menus were introduced that group related parameters under a single header. In this way, users only need to unfold groups of options that should be changed from their default values. 

Except for the File Upload Interface, the HADDOCK portals share the data structure, albeit that part of the variables is fixed to predefined values for the Easy and Expert interfaces. This has the advantage that they can all couple to a single back end CGI (Common Gateway Interface) script to handle the request, as will be discussed in more detail in the implementation details.

After issuing a request, the user is presented a link to a site where the progress can be followed. After the run is finished, the results can be viewed online and selected complexes or the complete output data of the run can be downloaded to a local machine.  

The use of the HADDOCK portal requires registration with a valid Grid certificate, giving a username and password. These are thereafter used to sign service requests. The requests themselves are handled using an eToken-based robot certificate, as is explained in more detail in the implementation details.

Links

 

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Cite WeNMR/WestLife

 
Usage of the WeNMR/WestLife portals should be acknowledged in any publication:
 
"The FP7 WeNMR (project# 261572) and H2020 West-Life (project# 675858) European e-Infrastructure projects are acknowledged for the use of their web portals, which make use of the EGI infrastructure and DIRAC4EGI service with the dedicated support of CESNET-MetaCloud, INFN-PADOVA, NCG-INGRID-PT, RAL-LCG2, TW-NCHC, SURFsara and NIKHEF, and the additional support of the national GRID Initiatives of Belgium, France, Italy, Germany, the Netherlands, Poland, Portugal, Spain, UK, South Africa, Malaysia, Taiwan and the US Open Science Grid."
 
And the following article describing the WeNMR portals should be cited:
Wassenaar et al. (2012). WeNMR: Structural Biology on the Grid.J. Grid. Comp., 10:743-767.

EGI-approved

The WeNMR Virtual Research Community has been the first to be officially recognized by the EGI.

European Union

WeNMR is an e-Infrastructure project funded under the 7th framework of the EU. Contract no. 261572

WestLife, the follow up project of WeNMR is a Virtual Research Environment e-Infrastructure project funded under Horizon 2020. Contract no. 675858

West-Life