Biomedical Engineering Reference
In-Depth Information
if molecules can move freely on surfaces. This has long been demonstrated exper-
imentally. As an example, when cells bearing CD2 surface molecules were micro-
manipulated into contact with surfaces coated with CD58, a ligand of CD2, either
in immobilized form or freely diffusing in a supported lipid bilayer, adhesion effi-
ciency was strongly increased when ligand molecules were mobile, and this effect
was more apparent when the ligand density was decreased [29]. As another example,
the adhesive efficiency of cell surface integrins was reported to increase in paral-
lel with lateral mobility, as measured with enhanced video microscopy and single
particle tracking [113].
Localization of binding molecules on surfaces.
As previously indicated, surface
roughness may strongly decrease the accessibility of surface receptors [196]. It is
understandable that this phenomenon might depend on the localization of bind-
ing molecules as suggested by some experimental evidence. Thus, the capacity of
selectin molecules to mediate binding of rapidly flowing leukocytes to the vessel
walls was found to require the localization of these selectins on the tip of cell surface
protrusions. Indeed, when this localization was prevented by changing the transmem-
brane domain of adhesion molecules, the dynamic binding capacity was abolished
although binding sites were intact [27] [190].
Interactions between soluble biomolecules are also environment-sensitive.
Recently,
the kinetics of DNA hybridation was studied in living cells transfected with
fluores-
cence resonance energy transfer
(FRET)-labeled double-strand DNA [173]. Differ-
ent kinetics were observed within cells and in the extracellular milieu, and differ-
ences were dependent on the length of strands. Further, the authors did not observe
any direct effect of molecular crowding
in vitro
. Other authors concluded on the basis
of experiments and computer simulation that the molecular crowding observed in the
cell interior might change protein conformation [87].
In conclusion
, the function of biomolecules involved in recognition events is
dependent on a wide spectrum of parameters that are not all determined by the struc-
ture of binding sites or event of linker parts of binding molecules. It is certainly
warranted to devote much attention to all these parameters in the forthcoming years.
1.5 RELATIONSHIP BETWEEN BIOMOLECULE STRUCTURE
AND RECOGNITION EVENTS
As shown in the previous sections, the efficiency and selectivity of biomolecule
interactions are dependent on a number of thermodynamic, kinetic, and mechanical
parameters that can be determined experimentally with exquisite sensitivity, using a
number of recently developed methodologies. These advances increase our need for
a theoretical framework, allowing us to relate these quantitative binding parameters
to structural properties. In addition to a mere intellectual appeal, such a framework
would be useful (1) to help us integrate a daunting amount of available data, (2)
to take advantage of increasingly available structural data to predict the interaction
behavior of important molecules, and (3) to facilitate the rational design of molecules
with desired interaction properties, for example, to act as drugs. In this section, three
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