Biomedical Engineering Reference
In-Depth Information
was 8 nM) after dimerization, while no measurable interaction was observed with
monomeric ICAM-1 [130]. It was further checked that ICAM-1 monomer expressed
a complete LFA-1 binding surface [102].
It is difficult to relate the properties of divalent and monovalent interactions
.As
emphasized above, it is because of this difficulty that single molecule studies rev-
olutionized our understanding of biomolecule interactions. This difficulty is due to
several reasons. Firstly, the rupture frequency of multivalent attachments may be
drastically decreased by the possibility of rebinding events. Indeed, while a monova-
lent attachment is expected to break spontaneously as a consequence of thermal fluc-
tuations, a multivalent attachment may need an external force for rupture if rebinding
occurs [178]. Also, the force sensitivity of multivalent attachments is strongly depen-
dent on force sharing between different bonds, and unbinding forces may follow a
number of different laws depending on forces and bond arrangement [177] [182]
[183].
In conclusion,
while single molecule studies essentially provided an accurate
description of the interaction between binding sites exposed by biomolecules, we
need to better understand the requirement for multivalent association. Clearly, mul-
tivalency is dependent on the topographical relationship between different bind-
ing sites and molecular flexibility. When interactions involve surface-attached
molecules, other additional factors are important, including static and dynamic
length and flexibility of linkers between surfaces and binding sites, as well as rugos-
ity of the surface region surrounding molecules, and lateral mobility of molecules.
These points will be briefly listed in a later section.
1.4.4 S
PECIFICITY OF
B
IOMOLECULE
I
NTERACTIONS:
A
N
E
SSENTIAL
P
ROPERTY
T
HAT
I
S
D
IFFICULT TO
D
EFINE
A
CCURATELY
Obviously, biomolecules must bind specifically to adequate targets to fulfil their task.
Specificity seems easy to define qualitatively. A ligand-receptor interaction is the
more specific as the interaction between the same receptor and a “slightly” different
ligand is “weaker.” However, there is no general way of defining the similarity of two
molecules or the strength of an interaction.
First, two molecules may differ according to their shape (e.g., as mentioned above
for ortho- or para-dinitrophenol), their electric charge, their hydrogen bonding capac-
ity, or their hydrophobicity. As indicated in the next section, all these properties are
involved in biomolecule recognition, but their relative importance may be different in
varying situations. The similarity (or dissimilarity) between two molecules is not an
absolute quantitative concept. This arbitrariness was indeed pointed out many years
ago [96].
Second, an interaction may be considered as “weaker” than another one if it
occurs less often under physiological conditions. Thus, the affinity constant may be
the dominant parameter if we are interested in the proportion of receptor molecules
that are occupied by their ligand at equlilibrium, for example, the number of insulin
receptors at a given moment. However, if we are interested in the detection of an
immobilized ligand on a surface dynamically explored by a cell protrusion, the
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