Interactive computer surface graphics approach to study of the active site of bovine trypsin

A descriptive medium for the presentation of protein structure has been developed and used to evaluate the structure of the active site of bovine trypsin (EC 3.4.21.4). This technique, involving advanced computer graphics technology, permits the facile display of a representation of the molecular surface of proteins of known structure and employs color to code the structural or chemical features of this surface. Benzamidine derivatives were inserted into the benzamidine-binding site of trypsin and the binary inhibitor-trypsin complex was evaluated by using the computer-generated structure. On the basis of qualitative assessments of the contribution of electrostatic and hydrophobic forces to the binding energy associated with complex formation, we made predictions concerning the effects of interaction of benzamidine substituents and amino acid side chains upon the binding energy associated with inhibitor-protein binding. The computer display of the molecular surfaces of the binary complex of substituted benzamidines and trypsin permitted unique insight into the identity and chemical properties of the atoms that participate at the interface of the molecular surfaces of the inhibitor and the protein. The computer-generated molecular surface display can potentially be combined with quantitative definition of the physical forces involved in the interaction of molecular surfaces. This technology should facilitate the study of the structure-activity relationship of substrates, inhibitors, and drugs that bind to proteins of known three-dimensional structure.