Abstract.Roughly 3/4 of human genomes are sequestered by nucleosomes, DNA spools with a protein core, dictating a broad range of biological processes, ranging from gene regulation, recombination, and replication, to chromosome condensation. Nucleosomes are dynamical structures and temporarily expose wrapped DNA through spontaneous unspooling from either end, a process called site exposure or nucleosome breathing. Here we ask how this process is influenced by the mechanical properties of the wrapped DNA, which is known to depend on the underlying base pair sequence. Using a coarse-grained nucleosome model we calculate the accessibility profiles for site exposure. We find that the process is very sensitive to sequence effects, so that evolution could potentially tune the accessibility of nucleosomal DNA and would only need a small number of mutations to do so.

Nucleosomes, DNA spools with a protein core, engage about three-quarters of eukaryotic DNA and play a critical role in chromosomal processes, ranging from gene regulation, recombination, and replication to chromosome condensation. For more than a decade, micromanipulation experiments where nucleosomes are put under tension, as well as the theoretical interpretations of these experiments, have deepened our understanding of the stability and dynamics of nucleosomes. Here we give a theoretical explanation for a surprising new experimental finding: nucleosomes wrapped onto the 601 positioning sequence (the sequence used in most laboratories) respond highly asymmetrically to external forces by always unwrapping from the same end. Using a computational nucleosome model, we show that this asymmetry can be explained by differences in the DNA mechanics of two very short stretches on the wrapped DNA portion. Our finding suggests that the physical properties of nucleosomes, here the response to forces, can be tuned locally by the choice of the underlying base-pair sequence. This leads to a new view of nucleosomes: a physically highly varied set of DNA-protein complexes whose properties can be tuned on evolutionary time scales to their specific function in the genomic context.

The sequence-dependent statistical mechanical properties of fragments of double-stranded DNA is believed to be pertinent to its biological function at length scales from a few base pairs (or bp) to a few hundreds of bp, e.g. indirect read-out protein binding sites, nucleosome positioning sequences, phased A-tracts, etc. In turn, the equilibrium statistical mechanics behaviour of DNA depends upon its ground state configuration, or minimum free energy shape, as well as on its fluctuations as governed by its stiffness (in an appropriate sense). We here present cgDNAweb, which provides browser-based interactive visualization of the sequence-dependent ground states of double-stranded DNA molecules, as predicted by the underlying cgDNA coarse-grain rigid-base model of fragments with arbitrary sequence. The cgDNAweb interface is specifically designed to facilitate comparison between ground state shapes of different sequences. The server is freely available at with no login requirement.

About three quarters of our DNA is wrapped into nucleosomes: DNA spools with a protein core. It is well known that the affinity of a given DNA stretch to be incorporated into a nucleosome depends on the geometry and elasticity of the basepair sequence involved, causing the positioning of nucleosomes. Here we show that DNA elasticity can have a much deeper effect on nucleosomes than just their positioning: it affects their "identities". Employing a recently developed computational algorithm, the mutation Monte Carlo method, we design nucleosomes with surprising physical characteristics. Unlike any other nucleosomes studied so far, these nucleosomes are short-lived when put under mechanical tension whereas other physical properties are largely unaffected. This suggests that the nucleosome, the most abundant DNA-protein complex in our cells, might more properly be considered a class of complexes with a wide array of physical properties, and raises the possibility that evolution has shaped various nucleosome species according to their genomic context.

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