Exploring the Conformational Space of DNA Kinks via Enhanced Sampling

DNA is a long biomolecule exstensively studied, most known for encoding the genome as a sequence of base-pairs. It also plays an active role in many biological processes which require DNA to interact with other biomolecules such as proteins. Proteins exert mechanical stresses and deform the DNA double-helix. In this thesis we focus on such type of deformation referred as a kink, a highly bent conformation of DNA that occurs at base pair level. Such kinks are not predicted from conventional theories such as Twistable Wormlike Chain Model (TWLC) which describes DNA as an harmonic chain with twist and bending elasticity. To describe kinks one needs to invoke anharmonic effects. More specifically we study the innate effect of DNA sequence on the DNA’s propensity towards kink formation. To this aim we use a novel algorithm (RBB-NA) designed to explore highly deformed structures of DNA in conjunction with molecular dynamics simulations of bare DNA to map out the free energy landscape as function of twist and roll. Twist and roll constitute two rotational angles characterising DNA’s configurational state at the base-pair level. The Weighted Histogram Analysis Method (WHAM) was employed to analyse the results and calculate the total free energy. The results support the initial hypothesis: not all sequences exhibit the same propensity for bending. Sequences known to form kinks when binding with proteins show a higher probability of kink formation. This study provides insights into the sequence-dependent mechanical properties of DNA and their role in protein-DNA interactions.