I have docked some ligands with target (protein). I observed that, ligands which have more hydrogen bonds and hydrophobic interactions with protein give poor binding energy (less negative). Ligands which have poor interactions ( less H-bonds and hydrophobic interaction), give good binding energy (highly negative). So how can I explain binding energy differences among the ligands? Which factors should be the main reason for explaining binding energy?
There could be several factors that affect the binding energy of ligands with a protein, and it is not possible to provide a definitive answer without more specific information about your system. However, some potential explanations for your observations are:
1- Ligand flexibility: Ligands that can adopt multiple conformations may have a higher chance of finding a low-energy binding pose with the protein, even if they do not have many favorable interactions. On the other hand, ligands that are rigid may have fewer conformations available to them, which could limit their ability to bind optimally to the protein.
2- Protein flexibility: Similarly, the protein may also have some flexibility that allows it to accommodate ligands that do not have many favorable interactions. In contrast, a more rigid protein may require specific interactions to form a stable complex with the ligand.
3- Solvent effects: The binding energy of a ligand also depends on the solvent environment, which can affect the stability of hydrogen bonds and hydrophobic interactions. It is possible that your more polar ligands are forming strong hydrogen bonds with water molecules, which could reduce their overall binding energy.
4- Entropy effects: Binding energy is not just a measure of the strength of the interactions between the ligand and protein; it also takes into account the loss of entropy that occurs when the two molecules bind. Ligands that form many strong interactions with the protein may have a larger entropy penalty than ligands that form fewer interactions, which could contribute to the observed differences in binding energy.
Overall, it is likely that a combination of these factors is contributing to the observed differences in binding energy between your ligands. To get a better understanding of the underlying mechanisms, you may want to perform additional analyses, such as molecular dynamics simulations or free energy calculations, to determine the relative contributions of each factor.
Thanks for your reply. It really helps to understand the factors. But I didn't understand the point, if more polar ligand makes strong hydrogen bonding, why it reduce overall binding energy?@Mudassir Alam
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