Presentations

Effect of A40S point mutation in histone H2A on nucleosome stability and dynamics: a molecular dynamics study

Kosarim N.A., Shaytan A.K.¹

Lomonosov Moscow State University, Faculty of Biology, Russia, 119234, Moscow, Leninskiye Gory, 1-12, E-mail: n.kosarim@intbio.org

¹Institute of Gene Biology, Russia, 119334, Moscow, 34/5 Vavilova St.

Histones are a key component of eukaryotic DNA packaging and are highly conserved. Even single amino acid substitutions in histones can significantly affect nucleosome structure and dynamics. One example is the H2A A40S substitution, which is found in some canonical H2A isoforms, the gene expression of which is downregulated in certain cancers [1]. Experimental data indicate that H2A A40S reduces nucleosome thermostability [2]. It has been suggested that this effect may be due to the disruption of hydrophobic interactions [3] and hydrogen bonds [4] between histones. However, the precise structural and dynamic mechanisms underlying nucleosome destabilization by this substitution remain incompletely understood.

Therefore, the aim of this work was to investigate the mechanisms of the H2A A40S substitution effect on nucleosome stability and dynamics using molecular dynamics simulations. We obtained and analyzed full-atom trajectories of wild-type and mutant (A40S) nucleosomes, with a total duration exceeding 4 microseconds.

The comparative modeling demonstrated that the H2A A40S substitution leads to nucleosome destabilization, manifested as more intense unwrapping of nucleosomal DNA. This effect is explained by a local reorganization of intranucleosomal interactions, which weakens the binding of histone H2B to DNA. This work was supported by the Russian Science Foundation grant No. 21-64-00001-П.

References.

1. Shah S. et al. Histone H2A isoforms: Potential implications in epigenome plasticity and diseases in eukaryotes // Journal of Biosciences. 45, 1, 2020, 4.

2. Tanaka, H. et al. Biochemical and structural analyses of the nucleosome containing human histone H2A.J. // The journal of biochemistry. 167, 4, 2020, 419–427.

3. Singh R. et al. Replication-dependent histone isoforms: a new source of complexity in chromatin structure and function // Nucleic acids research. 46, 17, 2018, 8665-8678.

4. Kosarim N. et al. Molecular dynamics simulations of nucleosomes containing histone variant H2A.J // International Journal of Molecular Sciences. 25, 22, 2024, 12136.

• abstract in Russian (PDF)