A multiscale analysis of DNA phase separation: From atomistic to mesoscale level

Abstract

DNA condensation and phase separation is of utmost importance for DNA packing in vivo with important applications in medicine, biotechnology and polymer physics. The presence of hexagonally ordered DNA is observed in virus capsids, sperm heads and in dinoflagellates. Rigorous modelling of this process in all-atom MD simulations is presently difficult to achieve due to size and time scale limitations. We used a hierarchical approach for systematic multiscale coarse-grained (CG) simulations of DNA phase separation induced by the three-valent cobalt(III)-hexammine (CoHex 3+ ). Solvent-mediated effective potentials for a CG model of DNA were extracted from all-atom MD simulations. Simulations of several hundred 100-bp-long CG DNA oligonucleotides in the presence of explicit CoHex 3+ ions demonstrated aggregation to a liquid crystalline hexagonally ordered phase. Following further coarse-graining and extraction of effective potentials, we conducted modelling at mesoscale level. In agreement with electron microscopy observations, simulations of an 10.2-kbplong DNA molecule showed phase separation to either a toroid or a fibre with distinct hexagonal DNA packing. The mechanism of toroid formation is analysed in detail. The approach used here is based only on the underlying all-atom force field and uses no adjustable parameters and may be generalized to modelling chromatin up to chromosome size.

A modern challenge of polymer physics: Novel ways to study, interpret, and reconstruct chromatin structure

“…For examples, quantum mechanics pictures describe nucleotide interactions at few base pairs resolution, focusing on their electronic properties, 22,23 while the so called "coarse-grained" models work at hundreds base pairs resolution and are very useful to study the 30 nm fiber in vivo with molecular mechanics approaches. 22,[24][25][26] At mesoscopic 22 or higher scales, classical polymer-physics-based models work typically at few hundreds or thousands base pairs resolutions, that is, where loops and TADs emerge [27][28][29][30] and confinement or torsional effects become relevant. 31 In this review, we will have a special focus on polymer-physics-based approaches.…”

Comparison of DNA force fields at a multiscale level : towards bottom-up modelling of chromatin

“…al. [162] have used a hierarchical approach for systematic multiscale CGMD simulations, predicting DNA phase separation in the presence of three-valent cobalt(III)-hexammine (CoHex 3+ ).…”

“…However, it needs to be mentioned a major approximation in the current multiscale approach is that the various effective potentials will be obtained from different all-atom simulations but will be used in a unified way in the final large-scale CG simulation and it is assumed that these potentials are transferable. This approximation is well justified [162]. To model the NCP and chromatin in a CG approach, all the interactions below are required and will be obtained from different all-atom simulations:…”

“…(C) Bonds and angles defined in the model, including the P-P bond added along the minor groove. Reproduced with permission from[162]…”

“…Figure 4.12: DNA phase separation into toroids using a super CG DNA model, based on the coarse-grained model presented above. Reproduced with permission from[162] …”