Effects of H2A Histone Variants on DNA Sequence and Nucleosome Structure using Coarse Grain Simulations

Abstract

Coarse grain molecular dynamics (CG-MD) simulations are seeing a rising tendency in a wide range of applications because their potential to enhance the sampling of all-atomistic simulations (AA-MD) and the capacity to make near-atomistic millisecond-timescale simulations practical, putting the second threshold on the horizon. In this field, the coarse-grained Martini force field has a prominent position and has recently extended its already range of applications to DNA-containing biomolecules [1].Eukaryotic genomic DNA exists as highly compacted nucleosome arrays called chromatin. Each nucleosome contains a 147-base-pair (bp) stretch of DNA, which is sharply bent and tightly wrapped around a histone protein octamer [2]. Several mechanisms regulate DNA accessibility, including replacement of canonical histones with specialized histone variants. Among the core histone variants, the H2A family is the biggest one -to date 5 histones variants are documented- showing also the highest sequence divergence among histone families. H2A variants show striking differences in three sites that are critical in intra- and inter-nucleosome interactions: the docking domain, which is close to the DNA entry/exit region, the L1 loop and the acidic patch, which is involved in nucleosome-nucleosome interactions. We have studied the structural and dynamic differences in those regions among H2A histone variants-containing nucleosome structures.Furthermore, it has been shown that DNA sequence effects vary between nucleosomes resulting in a significant factor in their stability. For this reason, we have also analyzed the differences in the associated DNA flexibility along the wrapped DNA sequence derived from MD simulations.