Molecular Recognition of Oligopeptides and Protein Surfaces - Designing Receptors for the Next Generation of Biosensors - page 66

Contents
1 Oligopeptide and Protein Surface Recognition ............................................. 68
1.1 Recognition of Short Peptides with Linear Receptors . . . . . . . . . . . . .................... 68
1.2 Di- and Multivalent Receptors for Peptide Recognition . ............................. 72
2 Protein Surface Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
2.1 Anionic Ligands . . . ..................................................................... 79
2.2 Cationic Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

1 Oligopeptide and Protein Surface Recognition

1.1 Recognition of Short Peptides with Linear Receptors

Following Lehn's description, the term “receptor” will be used throughout this
chapter as a chemical host which binds to a given guest [ 1 ]. According to this
definition, peptide receptors are synthetic organic molecules which selectively bind
to a peptide sequence via multiple non-covalent interactions. The molecular recog-
nition of short peptide sequences is a promising goal due to their importance in
biochemical and medicinal processes [ 2 ]. Artificial model systems may not only
contribute to the acquisition of a more substantial understanding of the yet not fully
understood molecular recognition process itself, but they may also serve as new
starting points for drug development [ 3 ] or as sensors for diagnostics [ 4 ]. A
prerequisite for potential applications is always a strong and selective complexation
of the target peptide sequence. In the following chapter, selected instructive
examples of oligopeptide receptors will be presented.
A well-studied example concerning a short peptide sequence of biological
importance is the amino acid sequence D -Ala- D -Ala-OH (1) and its depsipeptide
analog D -Ala- D -Lac-OH (2), which are both shown in Fig. 1 . The first one is crucial
for the mode of action of the antibiotic Vancomycin (3) against Gram-positive
bacteria: Vancomycin binds to this sequence with high affinity ( K 10 5 M 1 ),

thereby sterically blocking a transpeptidase enzyme from crosslinking the peptide
side chains of peptidoglycan strands, which act as precursors during bacterial cell
wall biosynthesis. This leads to a decrease of mechanical cell wall stability and
ultimately to lysis upon osmotic pressure changes. The depsipeptide 2 can be found
in Vancomycin-resistant bacteria: by exchanging an amide for an ester bond, the
complex stability is reduced by a factor of 1,000. This dramatic decrease is due to
the loss of one hydrogen bond, which is instead replaced by an electrostatic
repulsion between the oxygen lone pairs of the ester and the corresponding carbonyl
group in the antibiotic [ 5 ].
With the help of the combinatorial library 4 shown in Fig. 2 , comprising 39,304
members (343 proteinogenic and non-natural amino acids), Ellman was able to
identify receptors which bind to the depsipeptide sequence N,N 0 -Ac 2 - L -Lys- D -Ala-
D -Lac-OH (5) in aqueous solution [ 6 ]. The design of Ellman's receptor mimics that

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