Biology Reference
In-Depth Information
28
FOLDING OF CDR's AND PREDICTION OF ANTIBODY
COMBINING SITES
For a given amino acid sequence of a certain CDR of an antibody, predictive
methods will be explained in detail in Chapter 6 of how it may fold in three
dimension. Since the framework regions of most antibodies assume a
similar structure, they can form a foundation for the predicted CDR's to join
onto. Starting from the middle of the combining site, i.e. CDRH3 and
CDRL3, we can gradually build the entire structure of the six CDR loops.
The site generates a very compact and well-defined surface where the
antigen molecule can interact.
ANTIBODY DESIGN
Our understanding of the properties of protein surface structures is still very
limited. There may be patches of charged residues, three-dimensional
contours of various sizes and shapes, hydrophobic or hydrophilic areas, etc.
It will be important for us to describe them mathematically in order to get
some insight to the basic mechanisms of antibody-antigen interaction.
While we have localized the region of antibody molecules capable of
binding antigens, we still have no detailed knowledge of the basic forces
involved in such binding. To manufacture designer antibodies to bind
predefined antigens will be an extremely challenging area of study for the
joint effort of biologists and mathematicians.
APPLICATION TO OTHER PROBLEMS IN MOLECULAR
BIOLOGY
Variability plot can also be applied to any collection of homologous
proteins. Similar to antibodies, the T cell receptors (TCR's) for antigen can
also bind antigens in a somewhat different context. The TCR and chain
heterodimers bind processed peptides from foreign antigens sitting in the
grooves of major histocompatibility complex (MHC) class I or II molecules.
On the other hand, TCR chains can be MHC-restricted like chains,
or can be MHC-unrestricted. Variability plots for human TCR and chain
variable regions are shown in Figs. 1-16 and 1-17 (Johnson and Wu, 2000).
Their CDR3's are clearly indicated. However, their CDR1's and CDR2's
are uncertain, probably either due to the relatively few known amino acid
sequences or due to the less importance of these two CDR's.
