Drug self-assembly on DNA: Sequence effects with trans-bis-(4-N-methylpyridiniumyl)diphen porphyrin and hoechst 33258

Self assembly in biological systems is increasingly being recognised as an important phenomenon. We have examined two model systems: the cationic mese -substituted free base porphyrin derivative trans-bis-(4-N-methylpyridinium yl)diphenyl porphyrin (t-H2P) and Hoechst 33258 (Hoechst) both of which wer e known to assemble on DNA. t-H2P self-assembles in solution under appropri ate conditions, whereas Hoechst does not. By varying ionic strength and lig and:DNA mixing ratios, these features together with their different steric constraints have led to quite different DNA binding behaviour Hoechst on po ly[d(A-T)](2) stacks across the major groove? probably after filling its we ll established monomeric minor groove binding mode. By way of contrast the Hoechst/poly[d(G-C)](2) self-assembled aggregates involve partially interca lated molecules stacking in the major groove. The binding mode adopted by t -H2P with poly[d(A-T)](2) and poly[d(G-C)](2) appears to be kinetically con trolled and to be determined by the pre-existence of monomer binding and/or ligand stacks in solution. With poly[d(A-T)](2) the modes adopted both inv olve displacing the DNA bases to be more parallel than perpendicular to the helix axis. One is probably based on porphyrin intercalation and the other on minor groove binding. Resonance light scattering, linear dichroism, cir cular dichroism, normal absorption and fluorescence spectroscopies have bee n used to characterise the self-assembly in these systems.