Theoretical Analysis of the Stress Induced B-Z Transition in Superhelical DNA

Abstract

We present a method to calculate the propensities of regions within a DNA molecule to transition from B-form to Z-form under negative superhelical stresses. We use statistical mechanics to analyze the competition that occurs among all susceptible Z-forming regions at thermodynamic equilibrium in a superhelically stressed DNA of specified sequence. This method, which we call SIBZ, is similar to the SIDD algorithm that was previously developed to analyze superhelical duplex destabilization. A state of the system is determined by assigning to each base pair either the B- or the Z-conformation, accounting for the dinucleotide repeat unit of Z-DNA. The free energy of a state is comprised of the nucleation energy, the sequence-dependent B-Z transition energy, and the energy associated with the residual superhelicity remaining after the change of twist due to transition. Using this information, SIBZ calculates the equilibrium B-Z transition probability of each base pair in the sequence. This can be done at any physiologically reasonable level of negative superhelicity. We use SIBZ to analyze a variety of representative genomic DNA sequences. We show that the dominant Z-DNA forming regions in a sequence can compete in highly complex ways as the superhelicity level changes. Despite having no tunable parameters, the predictions of SIBZ agree precisely with experimental results, both for the onset of transition in plasmids containing introduced Z-forming sequences and for the locations of Z-forming regions in genomic sequences. We calculate the transition profiles of 5 kb regions taken from each of 12,841 mouse genes and centered on the transcription start site (TSS). We find a substantial increase in the frequency of Z-forming regions immediately upstream from the TSS. The approach developed here has the potential to illuminate the occurrence of Z-form regions in vivo, and the possible roles this transition may play in biological processes.

Theoretical Analysis of Competing Conformational Transitions in Superhelical DNA

“…Antibody binding experiments and SIBZ analysis of this plasmid has shown that it also contains several short Z-forming segments, the longest of which consists of 14 bp [31], [66]. Here we use the BDZ trans algorithm to analyze how these two transitions compete under various conditions.…”

“…Several algorithms have been developed to analyze superhelical transitions to a single type of alternate structure in DNA sequences where every base pair is regarded as being able to assume that structure [27]–[31]. A conformational state is determined by specifying which base pairs are in the B-form state and which are in the alternate structure.…”

DNA topology and transcription

“…64 Accordingly, in silico analyses showed a high enrichment of these sequences at regulatory regions of the genome and, notably, at the promoters of a wide range of oncogenes. [85][86][87][88] In addition, several conformation-sensitive proteins with regulatory function bind and stabilize non-B DNAs, suggesting an important role of these structures in transcriptional output. 64 Another way to make genetic processes more tolerant to the constrained DNA topology is weakening the DNA through introducing double strand breaks or nicks.…”

Theoretical and Experimental Investigations of DNA Open States

“…Этот вопрос исследовался при помощи Изинг-подобных подходов [33,35,[234][235][236][237][238][239], а также в радиально-торсионных моделях [175,176,240].…”

“…Очевидно, создавать нанобиоэлектронные устройства на основе релаксированной ДНК намного проще. Кроме того, открывание пузырьков само по себе способно приводить к частичному сбросу суперспирализационного напряжения [33][34][35]. Это дополнительно затрудняет сравнение расчётных данных с экспериментом.…”