Preparing ligands for docking can feel like a minor step, especially when your molecular modeling workflow is already complex. But overlooking ligand minimization can lead to misleading docking results and longer computation times. In this blog post, we’ll walk through when and why it’s important to minimize ligands before docking, based on the workflow in the AutoDock Vina Extended SAMSON Extension.
Why ligand minimization matters
Docking algorithms aim to predict how a ligand fits into a receptor’s binding site. But if your ligand starts in an unrealistic (high-energy or 2D) conformation, you might either get incorrect poses or waste time as the algorithm struggles to escape poor starting geometries.
Ligand minimization helps place your molecules in chemically reasonable 3D configurations before docking, ensuring smoother optimization and more credible binding predictions.
When it’s necessary
- Your ligand files come from 2D libraries or databases like ZINC — these often lack accurate hydrogen positions or 3D geometries.
- You suspect the input ligand geometry is strained or non-optimized.
- You want cleaner starting structures to avoid high RMSD values when comparing docked poses.
How to minimize ligands in SAMSON
In SAMSON, the AutoDock Vina Extended Extension allows for easy minimization of ligands — whether you’re working with a single ligand or a full library. This happens during the setup phase, and is configurable within a few clicks.
Simply check the Minimize option and select your desired preset (settings for number of steps and convergence criteria). You should also tick Add missing hydrogens unless you’re certain your ligands already include them. Polar hydrogens are important because the scoring function relies on detecting hydrogen bonding interactions.
Some important details
- You can minimize ligands directly as part of the dock preparation pipeline — no separate setup step needed.
- Minimization does NOT account for locked bonds. Bond rotatability constraints only apply during docking.
- If you’re working with ligands that include cis/trans isomers, make sure all relevant conformers are included in your library, as they will not be generated automatically.
Impact on docking results
Starting from minimized structures can reduce the likelihood of high-energy poses, ensure better fit within a binding site, and improve the reliability of scoring functions. It’s not a required step for every case, especially if your ligands have already been curated, but it is a recommended best practice for high-throughput virtual screening workflows.
If your docking results seemed inconsistent or underwhelming in terms of pose quality, introducing this simple step can make a difference.
To learn more about ligand preparation and minimization settings, check the full tutorial at this AutoDock Vina Extended documentation page.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at https://www.samson-connect.net.