Biomedical Engineering Reference
In-Depth Information
kinetic rate of bond formation may be more important. Finally, if we are interested
in the specificity of cell tethering on a surface, the interaction strength may be the
dominant parameter. Interestingly, these parameters are not necessarily correlated.
Thus, when mutant streptavidin molecules were made to bind to biotin, the rupture
forces were different, but they were correlated to the thermodynamic enthalpy rather
than free energy of reaction [36], which is tightly related to the affinity constant,
as recalled in Equation 1.2. Also, as mentioned above, the zero-force dissociation
rate may not be correlated to the force resistance as represented with Bell's distance
parameter [155] [162].
Third, the difficulty of defining specificity is further illustrated by the so-called
promiscuous
receptors that may bind specifically to a number of very different lig-
ands, while a slight alteration of a given ligand may abolish the interaction. As an
example, a monoclonal antibody was reported to bind specifically to 2,4 dinitrophe-
nol,
K
d
20 nM, with a negligible affinity for the close analogs 2-nitrophenol and
2-nitro-4-iodophenol (
K
d
=
M), but which also bound unrelated compounds
such as furazolidone with high affinity (
K
d
>
100
µ
M) [95].
In conclusion
, while it is recognized that both affinity and specificity are essential
properties of ligand-receptor interactions [96] [194], the latter may remain difficult
to define ambiguously. Specificity cannot be considered as an intrinsic parameter. A
receptor may be considered as specific for its ligand if it does not interact with other
molecules
that it is liable to encounter under biologically relevant situations.
The
significance of interaction specificity will be discussed more precisely in a further
section devoted to the structural basis of biomolecule interactions.
=
1
.
2
µ
1.4.5 L
IGAND
-R
ECEPTOR
I
NTERACTIONS
A
RE
I
NFLUENCED BY
P
ARAMETERS
T
HAT
A
RE
E
XTRINSIC TO
B
OTH
L
IGAND AND
R
ECEPTOR
M
OLECULES
In addition to the parameters we have just mentioned, it is important to recall that
molecular associations occurring in the biological milieu may be deeply influenced
by a number of external parameters that may obscure the intrinsic properties of inter-
acting sites. Receptor-mediated cell adhesion provides many examples as shown
below. We shall give selected examples to illustrate this point.
Presence of repellers on receptor-bearing surfaces.
It is well known that the surfaces
of living cells are coated with a carbohydrate-rich layer with a thickness of sev-
eral tens of nanometers or more, called the
glycocalyx
or
pericellular matrix
.Much
experimental evidence supports the view that (1) the glycocalyx may substantially
impair the receptor capacity to bind to ligands, particularly during short encounters
as occuring in a laminar flow chamber [142] [171], (2) under some circumstances,
cells may increase their receptor capacity by rapid removal of glycocalyx compo-
nents, thus increasing the accessibility of membrane receptors [172]. This inhibitory
effect of the pericellular matrix is an example of the so-called steric repulsion [151].
Lateral mobility of binding molecules.
It seems obvious that the probability of
encounter between surface-attached binding molecules may be strongly enhanced
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