Nucleic acid binding drugs. X. A theoretical study of proflavine intercalation into RNA and DNA fragments: comparison with crystallographic results

The minimum-energy structure for the interactions of the intercalation drug proflavine with the dinucleoside phosphates cytidylyl-3',5'-guanosine and deoxycytidylyl- 3',5'-deoxyguanosine have been found by means of a combination of computer graphics and empirical energy calculations. The minimum-energy positions for the drug, given the crystallographically observed nucleotide backbone conformations as starting points, are very close to the positions in the crystal structures of the complexes, with the intercalated proflavine molecule inserted from the majorgroove direction in each case. Alternative orientations for the drug were found to be much less stable. NMR studies in solution [Patel (1979). 2739-2754; Patel & Canuel (1977). Proc. Natl Acad. Sci. USA, 74, 2624-2628] are fully consistent with these observations. The finding in this study of close correspondence between observed and calculated structures for the drug complexes implies that the 'soft' parameterization of the force field used here, with its considerable advantages in computational speed over a more rigorous approach, may be especially helpful in combined molecular graphics and energetic approaches to drug-receptor binding.