Biomedical Engineering Reference
In-Depth Information
Table 1 Occurrence of amino acids of selected hit structures at each position of the receptor
Position
AA
1
AA
2
AA
3
AA
4
AA
5
AA
6
Amino acid
Gly (30%)
Ala (30%)
Val (40%)
Ala (40%)
Val (40%)
Ala (40%)
Met (50%) Met (40%)
His (30%)
Ser (70%)
reliable results. This indicates clearly that the resin influenced the binding events
occurring on the solid support. It is therefore crucial that results from measurements
involving resin-bound substances be verified in solution.
In conclusion, multivalent receptors have been proven to possess the potential to
increase both the selectivity and affinity of their binding to a defined substrate in
comparison with their one-armed analogs. By increasing the functional and struc-
tural diversity and “summing up” multiple non-covalent interactions, the competing
influence of the surrounding medium can be overcome. This is of special impor-
tance when working in water, which is necessary when biological targets are
involved. When designing such molecules several things have to be taken into
account. First, the template that bridges the arms plays a decisive role for the
complexation. Optimally it preorganizes the arms in a suitable fashion for binding
of the substrate and is still flexible enough to allow for its accommodation. For
peptide recognition by tweezer receptors, the distance and angle between the side
chains seems to be of utmost importance. Concerning the building blocks of the side
chains, amino acids offer valuable resources especially, when preparing combina-
torial receptor libraries, due to their diversity and commercial availability. Com-
monly the two arms are identical, as this facilitates the synthesis. Less well studied
are host systems with two different arms, although this approach offers the possi-
bility to add additional functionality. The introduction of a carboxylate binding site,
such as a guanidinium group, into the receptors has proven to be worthwhile for
improving binding properties. Other things that should be kept in mind are that
linkers and labels may also take part in the binding event, as can the solid support.
For this reason, it is advisable to always validate on-bead results with additional
measurements performed in solution.
2 Protein Surface Recognition
Proteins play a central role in many biological processes including metabolism,
regulatory activities, information transmission, transport, or as structural building
blocks for cells [
25
]. Their
primary structure
is determined by the sequence of their
building blocks, the 20 proteinogenic amino acids. Their size varies between 40 and
26,000 amino acids—with the majority having between 100 and 1,000 amino acids.
The local orientation of the polypeptide chain is called the
secondary structure
: the
a
-helix has a right-handed twist, contains 3.6 building blocks per turn, and thus has
a pitch of 0.54 nm. It is stabilized by an intra-strand hydrogen bond network, which
is formed between the
n
th C
¼
O and the (
n
+ 4)th NH groups of the polypeptide
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