A simple method to calculate the accessible volume of protein-bound ligands: application for ligand selectivity

We here present a method for estimating the accessible volume surrounding each atom of a ligand when bound to a receptor. The accessible volumes are calculated as the volume of a sphere with fixed radius, centered on each ligand atom, not simultaneously occupied by the volume of the receptor. The method is capable of describing the packing of the ligand in the binding pocket. Moreover, where structural models of several receptors in complex with the same ligand are available, a comparative study discriminating on accessible volumes can be performed. For these cases, a relatively large accessible volume in a particular receptor might indicate that this receptor has a unique cavity that might be exploited to develop a selective ligand analog. The ligand atoms showing variation in surrounding volume accessibility when bound to different receptors constitute attractive anchor points where one might want to attach substituents that modify the selectivity of the ligand. We have applied the described method to two different enzyme-ligand systems that bind tetrahydrobiopterin, i.e. the aromatic amino acid hydroxylases and nitric oxygen synthases. Our results yield new insights into the specificity of cofactor binding to these protein families.