Interaction of molecules with nucleic acids. II. Two pairs of families of intercalation sites, unwinding angles, and the neighbor‐exclusion principle

Intercalation‐site geometries are generated for a tetramer duplex extracted from B‐DNA. Glycosidic angles and puckers of the deoxyribose sugar groups bonded to base pairs BP 1 and BP 4 , namely, those at either end of the tetramer duplex, are assumed to be those of B‐DNA to insure continuity. All possible geometrical conformations for combinations of C(2′)‐ endo , C(3′)‐ endo , C(2′)‐ exo , and C(3′)‐ exo sugar puckers are determined for the tetranucleotide backbone. Those with minimum energy are selected as candidates for intercalation sites. Calculations reveal two pairs of physically meaningful families of intercalation sites which occur in two distinct regions, I and II, of helical angles which orient BP 2 relative to BP 3 and with the helical axis disjointed between these base pairs. For each site I and II within BP 2 and BP 3 , there are two distinct backbone conformations, A and B, connecting BP 3 to BP 4 or BP 1 to BP 2 which do not disrupt backbone conformations connecting BP 2 to BP 3 . Hence two pairs, IA and IB, and IIA and IIB, of intercalation sites exist in which the sugar puckers along the backbone of the tetramer alternate from C(2′)‐ endo to C(3′)‐ endo on the backbone (5′p3′) connecting BP 2 to BP 3 . The glycosidic angles of the C(3′)‐ endo sugar χ 3 γ are, coincidentally, 80° ± 2° for both conformations γ = A and B connecting BP 3 to BP 4 along the phosphate backbone (5′p3′). Consistent with the theoretical results, the experimental unwinding angles can be grouped into two categories with absolute values of 18° and 26°. The theoretical unwinding angles for sites IA and IB of 16° and for sites IIA and IIB of 20° occur for a displacement of ‐0.8 Å in the helical axes of BP 2 and BP 3 and for a 100% G·C composition, with a decrease depending on the amount of A·T base pairs present. Ratios of theoretical unwinding angles of sites I and II, which range from 0.75 to 0.84 for the two principal sites, compare well with the experimental value of 0.71. The theoretical results, in agreement with experimental observation, provide a new interpretation of the nature and conformation of the possible binding sites. Conformations obtained from these studies of intercalation sites in a tetramer duplex are used to rationalize the well‐known neighbor‐exclusion principle. The possibility of violation of this principle is demonstrated by the existence of two families of physically meaningful conformations. Conformations of unconstrained dimer duplexes are also obtained, one of which corresponds to the experimental crystal structure of ethidium–dinucleoside complexes, but these cannot be joined to the B‐DNA structure. Backbone conformations of the tetramer duplex can be constructed until the base‐pair separation reaches 8.25 Å, which may limit the molecules that can intercalate.