Energy Minimization of Structures

The YASARA module offers two different types of energy minimization: the protein structure's backbone can be kept either rigid or flexible, depending on the intended goal of the optimization.
The flexible option simulates adjustments in both the ligand and the target structure, resembling the simulation of an induced fit. When the rigid option is chosen, only the ligand is allowed to make further adjustments, focusing on bond lengths, bond angles, and its interactions with the target structure.

Both approaches can be used to minimize molecular torsions as well as inter- and intramolecular clashes, ultimately leading to refined structures with a lower level of free energy

Energy minimization can be used to gain further insights into a ligand-target complex. Through optimization, new interactions with side chains, the backbone, water molecules, metals, or co-complexed ligands may emerge, which can, in turn, positively impact the ligand's score. Such observations are advantageous when aiming to ensure that the best plausible pose of a ligand has been predicted.

Especially with smaller, fragment-like molecules, it is often challenging to predict the correct binding mode. In such cases, a subsequent optimization step following the prediction can provide additional confidence, as the positioning of the ligand has a significant impact on 3D design steps (extension, growing, merging, linking).

Energy minimization can also be utilized when the binding site of a structure is too small to host the ligand. Binding sites that are too narrow or virtually non-existent make docking predictions more challenging.

To simulate the induced fit of the target structure to the ligand, one can place the ligand in the binding site and temporarily tolerate clashes with the structure. By performing energy minimization afterward, both the ligand and the structure are allowed to adapt to each other (induced fit), thereby creating more space. In the example shown, clashes with the predicted model were successfully resolved after energy minimization.

Additional application scenarios:

• Generate space by expanding the ligand into potential subpockets.
• Overlay target subtypes or different X-ray structures to adapt a particular structure of interest to your ligand.
• Explore potential rotamers or combinations thereof that may expand the binding site size of your (apo) structures.
• Create space to host modalities to enable covalent docking.