Development of a Novel Coarse-Grained Model of the Nucleosome Core Particle for Long-Timescale Simulations

Abstract

The Nucleosome Core Particle (NCP) is the fundamental unit of DNA packaging in eukaryotic cells. It consists of ∼147 base pairs of DNA that are wrapped around an octameric protein core. Despite extensive experimental and theoretical work, the detailed physical mechanisms of important processes such as nucleosome opening, NCP-NCP interactions, and chromatin folding are not fully understood. Atomistic molecular dynamics (MD) simulations can in theory be a useful method to study these processes, however the timescales accessible to MD simulations are too short to explore these mechanisms. Therefore, we have used all-atom MD simulation data to derive a new Coarse-Grained (CG) model of the NCP. In this model, NCP residues are modeled using spherical beads centered on the DNA phosphorus and protein α-carbon atoms. DNA is represented by two types of beads that distinguish between base pairs (i.e. A-T and C-G), whereas protein residues are divided into two types based on their structure (i.e. α-helices and coils/loops). Force field parameters were derived using a hybrid approach of the iterative Boltzmann inversion method for bonded parameters, and Force Matching for non-bonded parameters. Our CG model significantly speeds up NCP simulations, and is expected to be useful in examining nucleosome opening, NCP-NCP interactions, and chromatin folding. Moreover, it is capable of reproducing the structural properties of the underlying atomistic system.