1CPN: A coarse-grained multi-scale model of chromatin

Abstract

A central question in epigenetics is how histone modifications influence the 3D structure of eukaryotic genomes and, ultimately, how this 3D structure is manifested in gene expression. The wide range of length scales that influence the 3D genome structure presents important challenges; epigenetic modifications to histones occur on scales of angstroms, yet the resulting effects of these modifications on genome structure can span micrometers. There is a scarcity of computational tools capable of providing a mechanistic picture of how molecular information from individual histones is propagated up to large regions of the genome. In this work, a new molecular model of chromatin is presented that provides such a picture. This new model, referred to as 1CPN, is structured around a rigorous multiscale approach, whereby free energies from an established and extensively validated model of the nucleosome are mapped onto a reduced coarse-grained topology. As such, 1CPN incorporates detailed physics from the nucleosome, such as histone modifications and DNA sequence, while maintaining the computational efficiency that is required to permit kilobase-scale simulations of genomic DNA. The 1CPN model reproduces the free energies and dynamics of both single nucleosomes and short chromatin fibers, and it is shown to be compatible with recently developed models of the linker histone. It is applied here to examine the effects of the linker DNA on the free energies of chromatin assembly and to demonstrate that these free energies are strongly dependent on the linker DNA length, pitch, and even DNA sequence. The 1CPN model is implemented in the LAMMPS simulation package and is distributed freely for public use.

Single-molecule and in silico dissection of the interaction between Polycomb repressive complex 2 and chromatin

“…The large size and complex protein-DNA contacts render chromatin a challenging system to study in silico. Although numerous coarse-grained models have been developed for chromatin structure characterization (28)(29)(30)(31)(32), they often lack sufficient molecular details necessary for describing the behavior of chromatin-binding complexes, especially those as intricate as PRC2. We applied a model with amino-acid and base-pair specificity to study protein-chromatin interaction at high chemical accuracy and structural resolution (33)(34)(35)(36)(37)(38).…”

Chromatin Compaction Multiscale Modeling: A Complex Synergy Between Theory, Simulation, and Experiment

“…In these cases, however, one needs to bear in mind that Hi-C maps, and sequencing techniques in general, often give an average picture of the genome. Ab initio models, on the other hand, take properties that have been observed or even hypothesized about chromatin as a starting point, and aim to reproduce them through the application of constraints and potentials (Tompitak, 2017;Lequieu et al, 2019). The mathematical nature of these models can sometimes lead to a simplification of biological factors at play.…”

Stability and folding pathways of tetra-nucleosome from six-dimensional free energy surface

“…The de Pablo group further introduced a systematic parameterization and coarse-graining procedure to derive mesoscopic models that are potentially of improved accuracy. 36 Here, we applied a near atomistic model to study the basic unit of chromatin fibers, the tetra-nucleosome. Protein and DNA molecules were represented with residue and base-pair resolution to provide a particle-based description of electrostatic interactions and specific protein-protein interactions that are crucial at stabilizing inter-nucleosome contacts.…”