To add to this, there’s an iterative set of interactions where ligand binding induces conformational changes on the receptor, which induces some conformational change on the ligand, and so on. That’s why in silico docking that assumes a rigid receptor often gives spurious results that don’t line up with experimentally measured binding affinities. It’s problematic since reductions in receptor degrees of freedom can impose a significant entropic cost, which can have a major influence on the Gibb’s free energy of the binding event.

We’re getting better at modeling those interactions than we used to be, but it’s still extremely challenging. The best efforts start with a large collection of known binding affinities with different ligands, which can be used to constrain the system.