In order to explore this problem, we performed state-of-the-art computer simulations with atomistic detail of several DNA molecules of different sequences. In our simulations we made use of a protocol that we have previously developed and which allows to incorporate an external force that acts to elongate the DNA (and any other system) in a controlled manner. In this way, one can obtain accurate measurements of the “spring constant” – or stretch modulus – of the system under study.
We initially performed the simulations at a low value of the stretching force (1pN) and found that the sequences substantially differed in their extension. Some helices appeared to be almost fully extended, while others seemed more compressed. This was found to be a consequence of an internal curvature of the DNA that we denoted crookedness. As we increased the force, sequences that were initially more compressed – or more crooked – were able to elongate by a greater amount that those that were already elongated at low forces. This revealed that the crookedness works as a reservoir of elastic energy that is directly encoded in the nucleotide sequence.
Remarkably, sequences that we found to lack this reservoir had been previously described to destabilize nucleosomes, the first step of DNA compaction into chromosomes. As a consequence, these DNA regions are known to be highly accessible to the cellular machinery, triggering many key biological processes. Our results support the idea that is the physical code that defines these regions. In other words, it is the unusual rigidity of these sequences, mediated by the crookedness, that confers them the ability to preclude their compaction into nucleosomes.
Of course, many fundamental questions remain open. How does this stretching flexibility relate to other forms of flexibility, such as twisting or bending? How is the crookedness involved in deformations at longer length scales? And more importantly, how is this physical code regulated at the genomic scale? These questions might reveal how cells make use of this physical code to neatly organize their huge amount of genetic information.