Bioorganic Chemistry
15
In addition to having antiviral properties,
which are probably linked to its ability to
inhibit the enzyme DNA polymerase, dis-
tamycin has found use as a template for
designing molecules with altered sequence
speciFcity and sequence-speciFc cleavage.
The binding of distamycin to the mi-
nor groove of double-stranded DNA in-
volves
the
combination
of
several
of
the previously described intermolecular
forces. These include (1) conformational
energy, (2) van der Waals’ interactions,
(3) hydrogen bonding, and (4) electrostatic
interactions. The minor groove of DNA
in the AT-rich regions to which dis-
tamycin binds is quite narrow, roughly
the width of a single carbon atom. The
distamycin molecule is composed of prin-
cipally sp
2
-hybridized (and approximately
planer) atoms. ±urthermore, uncomplexed
distamycin exhibits a slight twist. This
twist, brought about by subtle confor-
mational forces within the molecule, is
almost exactly the same as the twist ob-
served in the spiraling minor groove of
thedoub
lehe
l
ix
.Thus
,therearenoneo
f
the conformational energy penalties upon
binding as described previously. ±urther-
more, because the groove width is very
close to being the width of distamycin,
there is an opportunity for extensive van
der Waals’ interactions between the faces
of distamycin and the walls of the minor
groove. SpeciFc hydrogen bonds also play
an important role in the binding. In the AT-
rich regions of the minor groove to which
distamycin binds, there are exclusively hy-
drogen bond
acceptors
in the form of lone
pairs extending from nitrogens and oxy-
gens of the exposed edge of the nucleotide
bases. Distamycin in its natural conforma-
tion has exclusively hydrogen bond
donors
,
in the form of amide protons, directed
toward the floor of the minor groove. ±i-
nally, distamycin has a positively charged
amidinium group at one of its ends. This
contributes to the binding through electro-
static interaction with both the negatively
charged phosphate backbone and the lone
pairs on the minor groove floor.
The work of Dervan and others has
extended the sequences that can be specif-
ically targeted by minor groove–binding
molecules such as distamycin. So-called
hairpin polyamides that contain both the
pyrrole rings of distamycin as well as
the imidazole rings are able to bind to
sequences of DNA by speciFcally recog-
nizing and differentiating GC base pairs,
CG base pairs, and AT/TA base pairs.
The basis for this recognition is a side-
by-side binding motif, where two planer
oligomers (joined by a linker moiety) si-
multaneously bind to the minor groove
(±ig. 12). It should be noted that this bind-
ing could not have been easily predicted
from examining crystal structures of DNA,
as the minor groove in most of these is
far too narrow to accommodate two such
molecules. DNA is a dynamic molecule
and has been shown to be able to dis-
tort sufFciently to allow both molecules
to bind. Binding speciFcity is rooted in
the arrangement of pyrrole and imidazole
rings. As noted above, the floor of the
minor groove in AT regions of DNA is
exclusively hydrogen bond accepting, ex-
posing lone pairs of electrons with partial
minus charges. Regions of the side-by-
side hairpin polyamide that have a pyrrole
across from a pyrrole bind to these AT re-
gions, with hydrogen bonds being donated
from the amide NHs that are adjacent
to the pyrrole rings. Regions with GC or
CG base pairs are recognized by an im-
idazole/pyrrole pair or pyrrole/imidazole
pair respectively. This is because only G
has the ability to donate a hydrogen bond
(from an exocyclic NH) and only imidazole
(with the lone pair on the unprotonated
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