SynopsisA combined geometric and potential-energy analysis has been carried out to identify the torsional arrangements of the nucleic acid chain that can accommodate the intercalation of small planar moieties. In contrast to previous theoretical efforts, which detail local conformations after adjacent bases are positioned in space, the likely geometries are found here on the basis of the base orientations that result from all feasible combinations of the nine torsional variables of the basic dinucleotide intercalation unit. The relatively mobile nature of the sugar-phosphate backbone, together with the fairly long stretches of chemical bonds between adjacent units, is apparently responsible for the large number of feasible binding geometries. Some previously overlooked conformations with unusual sugar-puckering combinations and various phosphodiester arrangements are found in the survey. A large proportion of the energetically favored intercalation states are closely related to the backbone conformations of familiar double-helical models such as A-, B-, and Z-DNA, as well as the Watson-Crick model. Moreover, the intercalated forms are found to interconvert smoothly along a continuous conformational pathway. The intercalation structures derived from x-ray crystallographic analyses of drug-oligonucleotide complexes, in contrast, are stiff three-dimensional forms essentially frozen in a single domain of conformation space. Specific ligand-nucleic acid interactions that may he responsible for the experimental observations are not included in this study. The classical intramolecular potential energies reported here are highly approximate, providing only rough gauges of the relative importance of the many competing conformations.

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A theoretical model is proposed for the covalent binding of (+) 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene denoted by BPDE I(+), to N2 on guanine. The DNA must kink a minimum of 39 degrees to allow proper hybrid configurations about the C10 and N2 atoms involved in bond formation and to allow stacking of the pyrene moiety with the non-bonded adjacent base pair. Conservative (same sugar puckers and glycosidic angles as in B-DNA) and non-conservative (alternating sugar puckers as in intercalation sites) conformations are found and they are proposed structures in pathways connecting B-DNA, an intercalation site, and a kink site in the formation of a covalently intercalative bound adduct of BPDE I(+) to N2 on guanine. Stereographic projections are presented for (3') and (5') binding in the DNA. Experimental data for bending of DNA by BPDE, orientation of BPDE in DNA and unwinding of superhelical DNA is explained. The structure of a covalent intercalative complex is predicted to result from the reaction. Also, an anti----syn transition of guanine results in a structure which allows the DNA to resume its overall B-form. The only change is that guanine has been rotated by 200 degrees about its glycosidic bond so that the BPDE I(+) is bound in the major groove. The latter step may allow the DNA to be stored with an adduct which may produce an error in the genetic code.

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SynopsisA generalized procedure to generate nucleic acid structures is presented. In this procedure, the bases of a base pair are oriented first for characterization of particular DNA receptor sites. The resultant sites are then used in the study of specific molecule-DNA interactions. For example, intercalation sites, kinked DNA, and twisted and tilted bases are envisioned. Alterations of structures via anti-syn orientations of bases, as well as crankshaft motion about collinear bonds, provide additional conformations without disrupting the overall backbone structure. These approaches to the generation of nucleic acid structures are envisioned as required in studies of the intercalation phenomenon, minor adjustments of DNA to accommodate denaturation, binding of carcinogens to DNA, complex formation of transition metals with DNA, and antitumor agents as ligands. For these base-pair and base orientations, backbone orientations are calculated by the AGNAS technique to yield physically meaningful conformations, namely, those conformations for which nonbonded contacts are favorable. A procedure is presented to generate dimer duplex units that are physically meaningful and to assemble these units into a polynucleotide duplex. Double helices that begin with B-DNA, undergo a transition to one of the above-mentioned receptor sites, and return to B-DNA can be assembled from a catalog of dimer duplexes. Stereographic projections of the various receptor sites already being used to model binding to DNA are presented.