Nonplanar Aromatic Rings in Protein-Bound Ligands

Optimization of a ligand in a protein active site, especially if the protein conformation is held fixed during optimization, can often lead to distortions of the aromatic ring structures. Aromatic rings in optimized ligands are more prone to distortions when the initial pose structures are the output of docking, since tools such as OEDocking or POSIT try to accommodate a ligand into a rigid receptor pocket. Optimization of a ligand in the protein pocket helps relieve both intramolecular close contacts within the ligand and intermolecular clashes between the ligand and the protein. However, such relaxation of the van der Waals clashes can sometimes come at the expense of nonplanarity in the aromatic ring structures.

Ligand force fields used in optimization, such as Sage, Parsley, and MMFF, put a low energy constant in defining the out-of-plane potential of aromatic rings. The low energy penalty for aromatic rings to deviate from planarity in the force fields is also supported by quantum mechanical calculations which estimate only a 0.5 kcal/mol penalty for ~5 degrees of deviation for a benzene ring. The out-of-plane potential being the lowest vibrational motion during optimization means it can easily be bent by a few degrees during optimization.