Abstract
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 A 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 disulfide bonds,
ƒ¿-helices, and ƒÀ-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
ƒ¿-helices, bends, and ƒÀ-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 ƒ¿-helices, bends, and ƒÀ-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 A. Several methods for comparing conformations are also discussed;
in particular, comparisons between conformations of short segments are
carried out by a differential-geometry procedure.