Biomedical Engineering Reference
In-Depth Information
may strongly influence association rates. As an example, the association rate between
capsules bearing immunoglobulins and immunoglobulin receptors displayed 50-fold
decrease when a smooth erythrocyte was replaced with a rough nucleated cell [196].
In conclusion
, the new kind of information that was recently obtained on
biomolecule interactions by studying single bond formation and dissociation in the
presence of forces is directly relevant to a number of important biological processes.
However, connecting this information to structural data still requires significant the-
oretical and experimental progress. In addition, accounting for biological processes
still requires to consider other less well-defined parameters than
k
off
and
k
on
. Thus,
we shall briefly discuss the frequently used concepts of
avidity
and
specificity
.
1.4.3 A
VIDITY OF
B
IOMOLECULE
I
NTERACTIONS:
A
N
I
NCOMPLETELY
D
EFINED
P
ARAMETER
While aforementioned development might convey the view that ligand-receptor
interaction are liable to rigorous quantification, it has long been recognized that the
affinity constant or association rates did not fully account for biological phenomena.
Antigen recognition by antibodies provides a suitable example in view of the huge
diversity of interactions and number of applications in hospital and research labo-
ratory. As written in a standard treatise several decades ago [80] “In the literature,
affinity and avidity commonly are used synonymously ... However, it is now accepted
that the term affinity is a thermodynamic expression ... Avidity also involves other
contributing factors such as antibody valence, antigen valence.” A similar opinion
remains in use today [131] “... The total binding strength of a molecule with more
than one binding site is called the avidity.” Thus, although it is accepted that avidity
is not defined as accurately as affinity, a general concept is that this may be related
to the capacity of forming multivalent associations. Indeed, many situations suggest
that a most common way of forming strong associations involves the formation of
multiple bonds. The following examples are intended to support the importance of
the concept of avidity and the complexity associated to the multivalency of molecular
interactions.
Many biological interactions need to be multivalent
. There are many examples
suggesting that a single noncovalent interaction between a ligand and a receptor may
be too transient to be significant. Cell adhesion is driven by a number of membrane
receptors that often require multivalent interactions. Cadherins, which are thought
to play a dominant role in the stability of epithelia, are an important example. The
importance of lateral clustering was very elegantly demonstrated [199] by studying
the adhesion of cells expressing engineered cadherins, which could be oligomerized
at will by bridging the intracellular domains with a drug. Similarly, integrins play a
prominent role in cell adhesion to extracellular matrix components. It has long been
known that cell surface integrins are often in an inactive state, and events including
clustering or conformational changes are required to enable these integrins to bind
their ligands. Some recent examples clearly demonstrated that clustering integrins
could directly enhance the binding to multivalent, not monovalent ligands without
any affinity change [26]. As another example, ICAM-1, a ligand of integrin LFA-1,
was reported to bind to immobilized LFA-1 with high avidity (dissociation constant
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