Chemistry Reference
In-Depth Information
O
O
O
HO
O
HO
NH
NH
O
O
O
HN
HO
N
O
O
HN
HO
O
H
NH
NH
O
O
O
HN
NH
O
O
NH
O
O
HN
HN
O
O
H
2
N
NH
NH
O
NH
HN
HN
HO
HN
O
O
HO
O
O
O
O
N
N
N
HN
N
O
O
H
H
H
NH
O
NH
2
O
O
O
O
NH
NH
2
NH
O
O
HN
H
OH
O
HN
OH
O
O
D18B
O
O
O
N
O
N
N
N
H
NH
2
H
H
O
O
O
O
NH
NH
2
H
OH
O
L18
FIGURE 15.10
The third-generation peptide dendrimer
D18B
is resistant to trypsin diges-
tion, while its linear analog
L18
is rapidly cleaved.
peptide sequences using a customized topology manipulation kit. Low energy
conformers were generated by gradual cooling from 800 to 200 K from 20 different
starting high-energy conformations. The structural models obtained reproduced the
hydrodynamic radius determined by diffusion NMR across dendrimers of various
sizes and indicative of a molten globule state. Analysis of structural features in the low
energy conformers generated by MD showed only 0.3 backbone hydrogen bonds per
residue, which is much lower than the number of one backbone hydrogen bond per
residue found in secondary structure elements of folded proteins, and might explain
the conformational flexibility of peptide dendrimers.
The structural models of the single-site esterase peptide dendrimers
RG3
(AcTyrThr)
8
(DapTrpGly)
4
(DapArgSer)
2
DapHisSerNH
2
(AcIlePro)
8
(DapIleThr)
4
(DapHisAla)
2
DapHisLeuNH
2
produced by MD showed that the pair
of cationic residues at position X
3
(His or Arg) and the catalytic histidine residue at
position X
1
appear on the dendrimer surface. Docking of butyryloxypyrene trisulfo-
nate
and
HG3
showed the formation of at least one salt bridge between one of the substrate
sulfonate groups and one of the cationic residues at position X
3
on the dendrimer. In
addition, many low energy poses obtained by docking suitably positioned the reactive
ester group of substrate
1
in proximity to the catalytic histidine residue at X
1
in an
orientation suitable for esterolysis.
1
