Theoretical analysis of competitive conformational transitions in torsionally stressed DNA.

Abstract This paper presents a theoretical analysis of the conformation of a torsionally deformed segment of DNA containing two sites susceptible to stress-induced transitions in secondary structure. A mechanical analysis of the ensuing competitive behavior is developed and applied to several phenomena of possible biological relevance. First, a molecular lesion which disrupts base pairing without strand breakage (such as a pyrimidine dimer) is shown to provide an effective nucleation site for further stress-induced denaturation. A competition is established between strand separation at this lesion site and at the A + T-richest portion of the molecule. The relative importance of these two forms of melting is shown to depend upon the A + T-content of the sites involved, segment length, local environmental conditions and the magnitude of the imposed torsional deformation. A possible alternative mode of behavior of a stressed segment of DNA involves transitions from B-form to Z-form. The second application of this theory analyzes the interplay between B → Z transitions and local denaturation in torsionally stressed DNA. Finally, local melting is shown to be energetically preferred over transitions to A-form under physiologically reasonable conditions in vitro , due primarily to the greater degree of unwinding involved in melting. The mechanical theory presented here makes several simplifying assumptions regarding the nature of the transitions and the sequences involved. First, the theory is developed explicitly for the competition between two sites of possible transition, with no further consideration given to conformational degeneracy or sequence effects. These sites are regarded as being uniform in composition. A multistate, heteropolymeric statistical mechanical transition theory is required to account rigorously for degeneracy and the influence of base sequence. A preliminary formulation of such a theory is used to analyze the denaturation of a segment containing a site of disrupted base pairing.