Biology Reference
In-Depth Information
154
Other models may be constructed with the additional requirement of binding
Cu
++
(Honig
et al
., 1973).
Peptide Loops on Proteins
Typical examples of peptide loops on proteins are the complementarity
determining regions (CDR's) of antibodies discussed in Chapter 1.
Numerous amino acid sequences of CDR's have been determined during the
past 35 years. The method of predicting peptide backbone folding has been
applied to these sequences, and results in theoretically generating detailed
three-dimensional structures of antibody combining sites. An examples will
be illustrated here.
In this case, the three-dimensional structure of the framework regions of a
similar antibody is used as a scaffold. Structures of various CDR's are
predicted by matching sequences and angles to reference proteins, and
connected onto the scaffold. Therefore, the predicted loop folding must
have the N-terminal residue starting at a fixed position in space with a given
orientation. At the end of the loop, the C-terminal residue also has a fixed
location and orientation. Furthermore, steric hindrance should be avoided
not only within the same CDR loop but also among different CDR loops.
These restrictions are usually sufficient to reduce the possible theoretical
three-dimensional structures of the six CDR loops to just one or at most a
few choices.
This approach has been applied to immunoglobulin MOPC-315 (Stanford
and Wu, 1981). The known atomic coordinates of the framework regions
for another immunoglobulin Newm (Poljak
et al.,
1972; and the website,
http://www.rcsb.org/pdb)
were used as the scaffold.
For each CDR, the known angles of the amino acid residue
immediately to the N-terminal side is included to fix the location and
orientation of that end. In order to fix the location and orientation of the C-
terminal end, the known angles of the three amino acid residues
immediately after the CDR segment are also included. The choices of
the CDR amino acid residues are then adjusted to make sure that each CDR
loop can fit onto the scaffold. The criterion of fitting again depends on
minimizing a sum of squares. In this case, they are the distances between
experimental and theoretical locations of the atoms of the three amino
acid residues immediately after the C-terminal end of the CDR.
By
adjusting the
angles of the CDR amino acid residues and adjacent
