Microsecond molecular dynamics simulations of nucleosomes:implications for nucleosome functionстатьяТезисы
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Аннотация:Nucleosomes are elementary building blocks of chromatin compac- tion, where an octamer of histone proteins wraps about 200 base pairs of DNA into 2 super-helical turns. Initially nucleosomes were per- ceived as static structures whose sole function was to compact DNA. This view is now giving way to understanding of nucleosomes as in- trinsically dynamic entities, which actively participate in genome functioning and carry epigenetic markup complementary to the genetic code. The incorporation of different histone variants and post- translational modifications into nucleosomes may alter their struc- ture, dynamics and functions. To gain a deeper insight into the nucleosome function and understand the basic principles of its dy- namics we performed all-atom microsecond molecular dynamics (MD) simulations of nucleosomes including linker DNA segments and full-length histones in explicit solvent. We were able to identify and characterize the rearrangements in nucleosomes on a micro- second timescale including the coupling between the conforma- tion of the histone tails and the DNA geometry, as well as behavior of the flexible histone tails with respect to the nucleosomal and linker DNA. In addition we constructed structural models of vari- ant nucleosomes (H2A.Z-nucleosomes, centromeric nucleosomes, etc.), and analyzed their comparative dynamics, which we dis- cussed in context of recent experimental studies. MD simulations helped to elucidate the key physical principles of protein-DNA in- teractions in nucleosome and their implications for nucleosome dynamics and function. (Supported by the Intramural Research Programs of NLM and NCI; and RSF grant No. 14-24-00031 (nucleo- some visualization algorithms)).