Biomedical Engineering Reference
In-Depth Information
Other authors looked for more detailed estimates of the transfer free energy of
individual chemical groups from an apolar to an aqueous environment to obtain a
more accurate estimate of the energy of protein folding. The basic equation was
∑
i
Δ
F
=
g
i
A
i
(1.14)
Where the summation extends over all groups
i
of the solute, and
A
i
is the
conformation-dependent accessible surface area. The hydration free energy of chem-
ical groups such as
CH
3
, OH, or C=O was estimated at about 0.03, 0.29, and 0.72
k
B
T
A
2
, respectively [138].
In conclusion
, in this very brief review, we summarized some basic concepts
that are used as a crude framework to describe intermolecular forces. This will
be the starting point for a discussion of the basic mechanisms of ligand-receptor
association.
/
1.5.2 G
ENERAL
P
ROPERTIES OF
L
IGAND-
R
ECEPTOR
A
SSOCIATION
While it would certainly be quite naive to look for universal properties of
biomolecule interactions, it is useful to describe selected examples to help the reader
get a reasonably realistic feeling for involved mechanisms. As indicated above, we
shall essentially consider proteins.
1.5.2.1 A Static View of Ligand-Receptor Complexes
The contact area between two interacting proteins may be defined as the region that
was accessible in isolated molecules and that is no longer accessible in complexes
(assuming that the interaction did not trigger major morphological changes, which is
usually the case). In many cases involving membrane receptors or antibodies, molec-
ular association may result in a loss of accessible area comprised between about 800
and 1600
A
2
[39] [44] [101]. The interaction may involve between 10 and 30 side
chains from each protein [42]. Several questions are of interest:
Do all residues located in contact areas contribute a similar part to binding affinity?
The answer is probably negative, and extensive replacement of individual residues
was used to try and assess the relative importance of each interaction. In a pioneer-
ing study made on the interaction between human growth hormone and its recep-
tor [42] [47], it was concluded that more than 75% of the total binding energy was
accounted by a central hydrophobic region essentially involving two trp residues: the
replacement of each of these trp reduced the binding free energy by more than 7
k
B
T
[42]. It was thus concluded that a few
hot spots
contributed most of the interaction
energy. More recently, when a recombinant TCR was made to interact with a series of
nonapeptides bound by a same MHC molecule, the replacement of a single leucine
with a valine was sufficient to increase the binding free energy by 2
k
B
T
and pro-
voke a 3-fold decrease of the dissociation rate, and this difference resulted in nearly
10-fold change of T lymphocyte activation potency [4]. In a patient with a bleeding
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