The Role of Geometric Fit Between Protein Molecules and their Ligands in Determining Biological Specificity

The three-dimensional (3D) structure of most protein complexes reveals a close geometric match between those parts of the respective surfaces of the protein and the ligand that are in contact. In many cases the 3D structure of the components in the complex closely resembles that of the molecules in their free, native state. Geometric matching thus appears to play an important role in determining the structure of a complex. A geometric recognition algorithm was developed to identify molecular surface complementarity. It is based on a purely geometric approach and takes advantage of techniques applied in the field of pattern recognition. The algorithm provides a list of correlation values indicating the extent of geometric match between the surfaces of the molecules. The procedure is equivalent to a six-dimensional search, but is much faster by design, and the computations are only moderately dependent on the molecular size. The procedure was tested and validated by using five known complexes for which the relative position of the molecules in the respective adducts was successfully predicted. The molecular pairs were the α, β subunits of deoxy-hemoglobin and methemoglobin, tRNA synthetase-tyrosinyl adenylate, aspartate proteinase-peptide inhibitor, and trypsin-trypsin inhibitor. The algorithm developed is being extended to include electrostatic match and hydrophobic interactions. In view of the above findings, the parameters determining biological specificity on the molecular level are discussed and evaluated.