The final challenge identified pertains to the mapping of atoms that have large spatial distances from each other. This is particularly problematic when the input coordinates describe binding modes or specific desired 3D contexts. For small atom pair distances, the perturbation might be minimal and acceptable. However, for larger distances, a modified binding mode or incorrect stereochemistry might be sampled. This can be a significant issue in protein pockets, where the environment typically adapts slowly to ligands, and steric hindrance limits binding mode sampling.