Simulations of SIN mutations and histone variants in human nucleosomes reveal altered protein-DNA and core histone interactions

Alterations in the stability of a nucleosome exert predominant influence on chromatin structure and eukaryotic gene expression. In an attempt to investigate the mononucleosome stability using computational approaches, we have simulated the structure of a human mononucleosome and have compared their energies under the influence of core mutations, tail substitutions, variant histones, and orthologs. We observe that mutant nucleosomes carrying SIN (SWI Independent) mutations do not alter the overall nucleosomal structure but cause local structural changes leading to significant changes in energy and hence the stability. We observe that the nucleosome stability is altered by the substitution of only certain critical lysine residues on the H3 tails. Interestingly, the incorporation of variants H2A.Z and H3.3 lower nucleosome stability as evidenced by small energy changes. However, the substitution of histone orthologs did not alter structural stability. Our simulations to determine the nucleosome stability using energy trends emphasize the role of mutations, variants, and orthologs as determinants of chromatin structure at the nucleosome core particle level. The destabilization we observe on the human nucleosome with core mutations show similar trends of instability as validated experimentally in yeast.