The use of composite crystal-field environments in molecular recognition and the de novo design of protein ligands.

Small molecule crystal data have been retrieved from the Cambridge Crystallographic Database to compile composite crystal-field environments about different functional groups, which also occur in proteins and nucleotides. Their spatial distribution can be used to map-out putative interaction sites, e.g. about amino acid residues oriented towards the binding site of a given protein. Although influenced by packing forces, these composite environments show systematic patterns which reflect preferred interaction geometries of the functional groups under consideration with neighboring groups, e.g. hydrogen bonding partners. Similar but substantially less detailed distributions have been obtained from crystallographically determined ligand/protein complexes, which demonstrate that the properties observed in low-molecular weight structures are representative also for the sought after spatial orientation of interactions between ligands and their receptor proteins. The crystallographically determined binding geometries of three inhibitor/enzyme complexes are compared with the distributions of putative interaction sites predicted from corresponding composite field environments. In some cases, the observed positions of ligand atoms interacting with the proteins coincide with a region which is also frequently occupied by similar bonding partners in organic crystal structures, however, interaction geometries are also found which fall close to the limits of the ranges observed in the small molecule reference data. The information contained in the different composite crystal-field environments can be translated into rules which serve as guide-lines for automatic docking of small molecule fragments into the active site of proteins.