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Heather Gordon:
Research
Monte Carlo Simulations of Model Antibody Loops
Antibodies are proteins that form an important component of the defence
mechanism, or immune system, in the body. Our research will contribute
important knowledge for the successful engineering of novel antibodies for
the purposes of medical diagnostics or clinical applications. Our goal is
to understand better how the three-dimensional shape of antibodies contributes
towards their ability to recognise, bind, and thus target foreign substances
(antigens) for destruction. We do this by using computer simulations to
study the binding site of the antibody, called the "hypervariable loop region". At present, no one understands the
relationship between the inherently flexible nature of the antibody binding site
and its special ability to associate with individual antigens. The computer me
thods
and programs developed by this research will be of tremendous use to the emergi
ng
Canadian biotechnology sector.
It is accepted that the three dimensional shape of the antibody binding site
should match that of the antigen to which it binds. The ability of a unique ant
ibody
to target only a particular antigen, and the strength with which the antigen i bound, are both dependent on how well the respective shapes of the hypervariabl
e
loop region and the antigen match. While all antibody binding sites are compose
d of
six peptide loops, the chemical composition and lengths of those loops vary from
antibody to antibody. What is curious, is that the shape of an individual antib
ody
binding site is not fixed, but instead is very flexible! One might think, there
fore,
that a single antibody can adapt its binding site to fit many different antigen
s,
but this is not the case. Antibodies tend to be very specific in their binding
partners. So one important question is to determine the exact advantage that is
conferred by nature in designing a flexible rather than a fixed binding site. W
e
would also like to be able to control the flexibility of an individual antibody
binding site in order to optimize binding to its antigen. To both understand ansd
control the flexibility of the antibody binding site would be a tremendous asset
for
the improved design of antibodies that recognise novel antigens and/or that have
enhanced binding capabilities. The goal of our research is to develop computer
models for both predicting and describing the flexibility of both known and nove
l
antibody binding sites.
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