Study of the flexibility of DNA using molecular dynamics simulations

Biological processes manipulating DNA test its physical properties. Atomistic molecular dynamics simulations are a powerful tool to study the mechanical properties of DNA at atomic resolution, which is beyond the reach of single-molecule experiments. To deepen our understanding of these mechanical properties and their biological impact, a multi-approach combining simulations and experiments becomes crucial. Due to the lack of computational tools bridging these approaches, this thesis introduces two softwares for systematic analysis of nucleic acids structure and elasticity from numerical simulations, generating outputs compatible with single-molecule experiments. The first software, SerraLINE, allows the analysis of bending angle and compaction parameter distributions from simulations. We explored the structural effects of supercoiling on DNA minicircles. Our findings indicate the level of superhelical stress found in vivo induces DNA defects, providing a mechanism to relieve torsional stress and causing the shrinking of the molecule. SerraNA, the second software, provides local structural and flexibility parameters, along with global elastic constants, delivering a comprehensive mechanical description. Analysing the 136 unique tetramer sequences at the tetranucleotide length-scale reveals highly sequence and length-dependent elastic properties, with some sequences being 200% more flexible than others. Furthermore, exploring flexibility properties of complex DNA structures reveals that DNA-protein complexes are more rigid as proteins restrain the DNA into particular conformations, while DNA sequence mismatches act as flexible hinges. Additionally, we conducted a pioneering analysis of DNA elastic couplings as a function of length using SerraNA. We found that twisting and stretching deformations are coupled to bending through the roll, while tilt remains uncorrelated. Principal component analysis reveals that the transition from local to bulk flexibility is driven by a stretching mode at the length of 1.5 DNA turns. Our findings reveal that the DNA elastic couplings are intrinsic to essential movements and that these can yield opposite elastic couplings.