Computational Structural Biology group focusing on dissecting, understanding and predicting biomolecular interactions at the molecular level.

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# Small molecule docking

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Best practice guide

It’s possible to dock small ligands using HADDOCK but for that topology and parameter files for the ligand should be provided in CNS format. Several sources exist to find such files:

• the PRODGR server maintained by Daan van Aalten at Dundee University: https://prodrg2.dyndns.org
This server allows you to draw your molecule or paste coordinates and will return topologies and parameter files in various format, including CNS. You should turn on the electrostatic to obtain partial charges.

• the Automated Topology Builder (ATB) and Repository developed in Prof. Alan Mark’s group at the University of Queensland in Brisbane: https://compbio.biosci.uq.edu.au/atb

More detailed description is written in the frequently asked questions page. To get increase the chance of getting the right ligand conformation, one can perform ensemble docking. In this scenario multiple conformations can be generated as described here.

## Tutorials

• HADDOCK2.4 ligand binding site tutorial: A tutorial demonstrating the use of HADDOCK in ab-initio mode to screen for potential ligand binding sites. The information from the ab-initio run is then used to setup a binding pocket-targeted protein-ligand docking run. We use as example the multidrug exporter AcrB.

• Metadynamics: This tutorial highlights the benefits of enhanced sampling using metadynamics to improve the predictive power of molecular docking for protein-small molecule targets, in the case of binding sites undergoing conformational changes. For this, we will first generate an ensemble of conformers for the target protein using GROMACS and PLUMED, before proceeding with the docking using HADDOCK.

• HADDOCK covalent binding: This tutorial demonstrates how to use HADDOCK for the prediction of the three dimensional structure of a covalently bound ligand onto a receptor.

## Optimal settings for docking of small molecules

Parameter run.cns name default value optimal value
Clustering method  clust_meth FCC RMSD
Cutoff for clustering  clust_cutoff  0.6 2.5
Dieletric constant for it0  dielec_0 rdie cdie
Dieletric constant for it1  dielec_1 rdie cdie
Epsilon constant for the electrostatic energy term in it1  epsilon_1 1.0 10.0
Number of MD steps for rigid body high temperature TAD  initiosteps 500 0
Number of MD steps during first rigid body cooling stage  cool1_steps 500 0
Initial temperature for second TAD cooling step with flexible side-chain at the interface  tadinit2_t  1000 500
Initial temperature for third TAD cooling step with fully flexible interface  tadinit3_t  1000 300
Evdw 1  w_vdw_0  0.01 1.0
Eelec 3  w_elec_2  0.2 0.1

More about optimal settings for different docking scenarios can be found here.

## FAQ

A special section about docking of small molecules with HADDOCK is dedicated in the frequently asked questions page.