Bubble statistics and positioning in superhelically stressed DNA

Abstract

We present a general framework to study the thermodynamic denaturation of double-stranded DNA under superhelical stress. We report calculations of position- and size-dependent opening probabilities for bubbles along the sequence. Our results are obtained from transfer-matrix solutions of the Zimm-Bragg model for unconstrained DNA and of a self-consistent linearization of the Benham model for superhelical DNA. The numerical efficiency of our method allows for the analysis of entire genomes and of random sequences of corresponding length ($10^6-10^9$ base pairs). We show that, at physiological conditions, opening in superhelical DNA is strongly cooperative with average bubble sizes of $10^2-10^3$ base pairs (bp), and orders of magnitude higher than in unconstrained DNA. In heterogeneous sequences, the average degree of base-pair opening is self-averaging, while bubble localization and statistics are dominated by sequence disorder. Compared to random sequences with identical GC-content, genomic DNA has a significantly increased probability to open large bubbles under superhelical stress. These bubbles are frequently located directly upstream of transcription start sites.