Simulating the Entropic Collapse of Coarse-Grained Chromosomes

Abstract

Depletion forces play a role in the compaction and decompaction of chromosomal material in simple cells, but it has remained debatable whether they are sufficient to account for chromosomal collapse. We present coarse-grained molecular dynamics simulations, which reveal that depletion-induced attraction is sufficient to cause the collapse of a flexible chain of large structural monomers immersed in a bath of smaller depletants. These simulations use an explicit coarse-grained computational model that treats both the supercoiled DNA structural monomers and the smaller protein crowding agents as combinatorial, truncated Lennard-Jones spheres. By presenting a simple theoretical model, we quantitatively cast the action of depletants on supercoiled bacterial DNA as an effective solvent quality. The rapid collapse of the simulated flexible chromosome at the predicted volume fraction of depletants is a continuous phase transition. Additional physical effects to such simple chromosome models, such as enthalpic interactions between structural monomers or chain rigidity, are required if the collapse is to be a first-order phase transition.

Effects of molecular crowding and confinement on the spatial organization of a biopolymer

“…For instance, a computational approach has shown the interplay between crowder size and density in collapsing a flexible chain in a cylindrical space 16 . The compaction in this case appears to be continuous, similarly to a corresponding unconfined case 17,18 . More recently, the interdependence of chain length and compaction has been discussed 20 .…”

“…Thanks to recent efforts, several key features of chain collapse by molecular crowding have begun to emerge 8,[16][17][18][19][20] . For instance, a computational approach has shown the interplay between crowder size and density in collapsing a flexible chain in a cylindrical space 16 .…”

“…In our simulations, a c ranges between 0.2a and 20a, and the number of monomers can be as large as N = 2, 000. * The small-a c case (a > a c ) may represent a coarse-grained model of the bacterial chromosome [16][17][18] , in which each monomer represents a 'structural unit' or 'topological domain,' inside which supercoiled DNA is stabilized by proteins [6][7][8] (see Fig. 1(a)).…”

Molecular simulations of cellular processes

“…Macromolecular crowders are unlikely to be the only determinants of chromosome compaction, as Shendruk et al (2015) concluded from observing a continuous rather than first-order transition as in experiments (Pelletier et al 2012). One such factor, i.e., DNA binding proteins (DBPs), has been studied by Brackley et al (2013b).…”

“…Accordingly, crowders have often been modeled as inert hard spheres to capture the effect of volume occlusion. This approximation has led to the prediction that inert crowders promote folding and chemical reactions (Muramatsu and Minton 1988;Zhou et al 2008), as well as to observing the reversible transition from a swollen to a compact chromosome (Shendruk et al 2015) and the assembly of nuclear bodies in computer simulations (Cho and Kim 2012b;Kim and Szleifer 2014).…”