JOINT MOLECULAR MODELING AND SPECTROSCOPIC STUDIES OF DNA COMPLEXES OF A BIS(ARGINYL) CONJUGATE OF A TRICATIONIC PORPHYRIN DESIGNED TO TARGET THE MAJOR GROOVE
S. Mohammadi et al., JOINT MOLECULAR MODELING AND SPECTROSCOPIC STUDIES OF DNA COMPLEXES OF A BIS(ARGINYL) CONJUGATE OF A TRICATIONIC PORPHYRIN DESIGNED TO TARGET THE MAJOR GROOVE, Biochemistry, 37(17), 1998, pp. 6165-6178
To target selectively the major groove of double-stranded B DNA, we ha
ve designed and synthesized a bis(arginyl) conjugate of a tricationic
porphyrin (BAP). Its binding energies with a series of double-stranded
dodecanucleotides, having in common a central d(CpG)(2) intercalation
site were compared. The theoretical results indicated a significant e
nergy preference favoring major groove over minor groove binding and a
preferential binding to a sequence encompassing the palindrome GGCGCC
encountered in the Primary Binding Site of the HIV-1 retrovirus. Spec
troscopic studies were carried out on the complexes of BAP with poly(d
G-dC) and poly(dA-dT) and a series of oligonucleotide duplexes having
either a GGCGCC, CCCGGG, or TACGTA sequence. The results of UV-visible
and circular dichroism spectroscopies indicated that intercalation of
the porphyrin takes place in poly(dG-dC) and all the oligonucleotides
. Thermal denaturation studies showed that BAP increased significantly
the melting temperature of the oligonucleotides having the GGCGCC seq
uence, whereas it produced only a negligible stabilization of sequence
s having CCCGGG or TACGTA in place of GGCGCC. This indicates a prefere
ntial binding of BAP to GGCGCC, fully consistent with the theoretical
predictions. IR spectroscopy on d(GGCGCC)(2) indicated that the guanin
e absorption bands, C-6=O-6 and N-7-C-8-H, were shifted by the binding
of BAP, indicative of the interactions of the arginine arms in the ma
jor groove. Thus, the de novo designed compound BAP constitutes one of
the very rare intercalators which, similar to the antitumor drugs mit
oxantrone and ditercalinium, binds DNA in the major groove rather than
in the minor groove.