Distance-constraint approach to protein folding. II. Prediction of three-dimensional structure of bovine pancreatic trypsin inhibitor

The possibility of predicting the three-dimensional structure of bovine pancreatic trypsin inhibitor (BPTI) is examined using a distance-constraint approach. The mean distances between the amino acid residues in globular proteins, calculated in a previous paper, are utilized as distance constraints. In this study, as in previous work of others, root-mean-square deviations of the predicted conformations from the native one of less than 4 Å could not be obtained if the only input information consisted of the mean distances between amino acid residues (which involve information about the hydrophobicity and hydrophilicity of each amino acid residue) and the locations of disuifide bonds, α-helices, and β-structures. An examination is made of the kinds of structural features of BPTI that appear in the conformations predicted without explicit inclusion of information about such structural features, and of the kinds of information required in a given set of distance constraints for successful folding of BPTI. For example, structures that resemble incipient-forming α-helices, bends, and β-structures are observed in the conformations predicted when only the mean distances between the amino acid residues and the locations of the disulfide bonds (without information about the locations of α-helices, bends, and β-structures) are used. One type of additional required information is knowledge of spatially distant pairs involving the active site and the terminal residues. Furthermore, examination of the missing information indicates an important role for the strong nonbonded interaction between sulfur atoms and the side chains of aromatic amino acid residues in BPTI. When such information is introduced into the set of distance constraints, in terms of the exact distances of five pairs, (which implicitly include sulfur/aromatic interactions), the root-mean-square deviations of the predicted conformations decrease to 2.2-3.2 Å. Several methods for comparing conformations are also discussed; in particular, comparisons between conformations of short segments are carried out by a differential-geometry procedure.