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-kb-long 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 generalised to modelling chromatin up to chromosome size.

Bottom-Up Coarse-Grained Modeling of DNA

“…where ϵ 0 is the vacuum permittivity, ϵ is the relative permittivity. It is used in the IMC dsDNA model (Korolev et al, 2014 ; Sun et al, 2019 ; Minhas et al, 2020 ), the MRG-CG model (Savelyev and Papoian, 2009a , 2010 ), the “sugar” model for its ion-ion and ion-DNA interactions (Kovaleva et al, 2017 ), and a few other models. Some models use the Debye-Huckle potential, generally in the form (Savelyev and Papoian, 2009b ; Morriss-Andrews et al, 2010 ; He et al, 2013 ; Hinckley et al, 2013 ; Kovaleva et al, 2017 )…”

“…In a simplified representation, DNA base pair interactions can be approximated by bonded fluctuations, as done in the IMC dsDNA model (Korolev et al, 2014 ; Sun et al, 2019 ; Minhas et al, 2020 ) and the G-quadruplex model by Rebič et al ( 2015 ). Though the details of basepair conformation and dynamics are lost, these representations are incredibly efficient in simulation and are easily extended to large molecules.…”

“… Graphical representation of selected bottom-up coarse-grained DNA models. (A) the IMC DNA model (Sun et al, 2019 ; Minhas et al, 2020 ). Electrostatic interaction is modeled with explicit ion and phosphate beads (red), in addition to its apparent double-helical structure.…”

“…In a recent effort to implement a full bottom-up model and extend the application range of this model, Sun et al ( 2019 ) have recalculated all interaction potentials for DNA and a number of mono- and multivalent ions by IMC, both bonded and non-bonded. The fine-grained simulation was conducted with four segments of 36-bp dsDNA, described by the CHARMM27 force field.…”

“…A further step of coarse-graining was conducted based on this CG DNA model, producing a mesoscale DNA model (Sun et al, 2019 ), which showcases the inherent convenience of performing multiscale modeling with bottom-up coarse-graining methods. In this mesoscale model, the dsDNA chain is represented by a chain of spherical beads, each bead representing six base pairs of dsDNA.…”