DNA sliding in nucleosomes via twist defect propagation revealed by molecular simulations

Abstract

While nucleosomes are highly stable structures as fundamental units of chromatin, they also slide along the DNA, either spontaneously or by active remodelers. Here, we investigate the microscopic mechanisms of nucleosome sliding by multiscale molecular simulations, characterizing how the screw-like motion of DNA proceeds via the formation and propagation of twist defects. Firstly, coarse-grained molecular simulations reveal that the sliding dynamics is highly dependent on DNA sequence. Depending on the sequence and the nucleosome super-helical location, we find two distinct types of twist defects: a locally under-twisted DNA region, previously observed in crystal structures, and a locally over-twisted DNA, an unprecedented feature. The stability of the over-twist defect was confirmed via all-atom simulations. Analysis of our trajectories via Markov state modeling highlights how the sequence-dependence of the sliding dynamics is due to the different twist defect energy costs, and in particular how nucleosome regions where defects cannot easily form introduce the kinetic bottlenecks slowing down repositioning. Twist defects can also mediate sliding of nucleosomes made with strong positioning sequences, albeit at a much lower diffusion coefficient, due to a high-energy intermediate state. Finally, we discuss how chromatin remodelers may exploit these spontaneous fluctuations to induce unidirectional sliding of nucleosomes.

Nucleosomal DNA dynamics mediate Oct4 pioneer factor binding

“…In addition to breathing, the PCA revealed overtwisting motions of the nucleosomal DNA (Movie S1), which are notoriously difficult to quantify. Previously, these were characterized by monitoring the changes in the contacts of selected arginine residues 23 or the change of the basepair orientation relative to the nucleosome superhelical axis 15 . Both approaches have important limitations.…”

“…Nevertheless, all these previous atomic resolution MD simulations 19 were started from the most complete crystal structure of the nucleosome 20 , using a palindromic DNA sequence derived from human α-satellite DNA. Interestingly, coarse-grained MD simulations, in which several non-hydrogen atoms are grouped in beads have been performed with different DNA sequences [21][22][23] . Many of these studies used the Widom 601 artificial sequence 22,24 , an artificial sequence selected for its stability 25 that is present in many crystal structures of the nucleosome 26,27 .…”

Mechanism of Dynamic Binding of Replication Protein A to ssDNA

“…The mechanism, referred as 'reptation dynamics', has been captured experimentally (25) although the formation of bulges is not. The picture is reminiscent of sliding mechanism of dsDNA on nucleosome via twist defect propagation (26).…”

Capturing Protein-Ligand Recognition Pathways in Coarse-grained Simulation

“…Recently, coarse-grained models are also being extended to study ribosome dynamics 25 and various protein-DNA transient complexes. [26][27][28] Motivated by these success stories of coarsegrained models, we speculated if coarse-grained models of proteins and small molecules can be put into play to substitute computationally expensive all-atom simulations for capturing protein-ligand recognition process on the fly. In this work, by building on popular MAR-TINI 6,29-31 coarse-grained frame-work, we report that while its vanilla implementation on protein-ligand system might fail to capture the binding event, judicious optimization of elastic network 32 in MARTINI protein model enable the simulation of the spontaneous binding process of ligand to the designated cavity at crystallographically identical pose.…”