Exploration of Configurational and Topological Properties of Minichromosomes using Elastic Energy Optimizations at the DNA Base-Pair Level

Abstract

Advances in experimental biophysics continue to broaden our understanding of protein-DNA interactions, highlighting structural characteristics that may account for modes of genetic expression and regulation. These interactions influence the configuration of DNA that enters and exits the protein and may lead to DNA supercoiling. Previous studies of minichromosomes showcased discrepancies in linking number and topology across short circular chains containing nucleosomes with ∼145 base-pairs of DNA wrapped less than two superhelical turns around a core of eight histone proteins. The increasing collection of high-resolution nucleosome structures has been valuable in developing computational models to survey differences in minichromosomes with different histone binding surfaces or DNA sequences. The models offer an approximation of the energetically favorable configurations of protein-free DNA, which depend on the spatial arrangements of the entry and exit base-pairs and/or the nucleotide sequence. Elastic energy minimization calculations performed at the level of base-pair steps starting from approximately closed circular DNA models generated by Monte Carlo sampling have revealed the sensitivity of minichromosomal configurations to free-DNA chain length, entry-exit spatial arrangements, and imposed base-pair twist. Producing optimized circular structures on a mesoscale level may shed light on certain topological behaviors, such as strand crossings at the entry and exit regions of linker DNA, and may reconcile the linking number paradox that surround minichromosomes.