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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Hybrid methods to characterize nucleosome structure and dynamics with high precision

Nucleosomes are basic units of chromatin compaction and hubs in epigenetic signaling pathways. Nucleosomes experience a broad repertoire of alterations that affect their dynamics and interactions with various binding partners. To gain insights into intrinsic dynamics of the full nucleosome, we performed all-atom microsecond molecular dynamics simulations of nucleosomes including linker DNA segments and full-length histones [1]. Next, we developed several hybrid approaches by combining experimental data with molecular modeling and molecular dynamics simulations.

First approach, HYDROID, allows interpretation of DNA-protein interactions by quantifying Hydroxyl Radical Footprinting data and integrating it with atomistic structural models [2]. We applied HYDROID to characterize Saccharomyces cerevisiae centromeric nucleosome of unknown structure and identified the precise positioning of centromeric DNA sequence [3]. In another study we used HYDROID to pinpoint the footprint of interaction between the inner kinetochore protein Mif2/CENP-C and centromeric DNA which plays an important role for Mif2 recruitment [4].

Our second hybrid approach was applied to describe histone octamer distortion preceding DNA entry into nucleosomes and processive movement of the ATPase motor of ISW2 on nucleosomal DNA. We performed accelerated molecular dynamics simulations guided by experimental chemical crosslinking data to gain an understanding of the potential perturbations occurring in the nucleosome structure and investigate how nucleosomal DNA can adjust to perturbations in the histone octamer structure.



anna-fig.gif References

    1. Shaytan, A.K., Armeev, G.A., Goncearenco, A., Zhurkin, V.B., Landsman, D., and Panchenko, A.R. (2016). Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions. J Mol Biol 428, 221-237.

    2. Shaytan, A.K., Xiao, H., Armeev, G.A., Gaykalova, D.A., Komarova, G.A., Wu, C., Studitsky, V.M., Landsman, D., and Panchenko, A.R. (2018). Structural interpretation of DNA-protein hydroxyl-radical footprinting experiments with high resolution using HYDROID. Nat Protoc 13, 2535-2556.

    3. Shaytan, A.K., Xiao, H., Armeev, G.A., Wu, C., Landsman, D., and Panchenko, A.R. (2017). Hydroxyl-radical footprinting combined with molecular modeling identifies unique features of DNA conformation and nucleosome positioning. Nucleic acids research 45, 9229-9243.

    4. Xiao, H., Wang, F., Wisniewski, J., Shaytan, A.K., Ghirlando, R., FitzGerald, P.C., Huang, Y., Wei, D., Li, S., Landsman, D., et al. (2017). Molecular basis of CENP-C association with the CENP-A nucleosome at yeast centromeres. Genes Dev 31, 1958-1972.

Anna Panchenko

National Center for Biotechnology Information
National Library of Medicine
National Institutes of Health
Bethesda, MD, USA 20894

e-mail: panch@ncbi.nlm.nih.gov