Theoretical design of a bis-orthopepetide derivative of a tetracationic porphyrin targeted toward a six-base pair sequence of DNA.
Tetra-(4-N-methylpyridyl)-porphyrin, (T4MPyP), is a tetracationic porphyrin that binds to G-C sequences of DNA by means of an intercalative mode. In order to extend its selective sequence recognition capacity for bases beyond the intercalation site, and in the major groove, we have undertaken the theoretical design of bis-ortho peptide derivatives of T4MPyP. In these, two ortho N-methylpiperidinium nitrogens are linked to a cationic residue, L-Lys, L-Orn, or L-Arg. The binding energetics of these novel compounds were compared for six distinct double-stranded palindromic hexanucleotide sequences. Four distinct modes of binding were compared: a) major, b) minor groove binding of both peptidic arms; c) a straddling mode in which each arm is in a different groove of DNA; d) exclusive binding of the arms to the sugar-phosphate backbone. For our most promising compound, that with Lys side-chains, a distinctive energetical advantage was computed in favor of an all-major groove binding to sequence d(CCCGGG)2. The corresponding complex is separated by an energy gap of 12 kcal/mol, with respect to the second-best sequence bound in the major groove, d(GGCGCC)2, and of 20 kcal/mol with respect to minor groove binding to sequence d(TACGTA)2. The results obtained with such a prototypic compound indicate that it is fully possible to design sequence selective (> 6 base-pairs) photosensitizers as peptide derivatives of T4MPyP and prompt the engineering of further, more complex analogs thereof.
Hui
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Laboratoire de Biochimie Théorique, Institute de Biologie Physico-Chimique, Paris, France.
Gresh
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D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D011166:Porphyrins / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D009838:Oligodeoxyribonucleotides; D010710:Phosphates; D011166:Porphyrins; C021096:tetra(4-N-methylpyridyl)porphine; D004247:DNA