Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Friday Speaker Abstracts

BREATHS, TWISTS, AND TURNS OF FREE AND INTERACTING ATOMISTIC NUCLEOSOMES Vlad Cojocaru 1,2,3 ; Jan Huertas 2 ; Caitlin MacCarthy 2 ; Hans Schoeler 2 ; 1 Hubrecht Institute, In Silico Biomolecular Structure and Dynamics, Utrecht, The Netherlands 2 Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Muenster, Germany 3 Babes Bolyai University, Faculty of Geology and Biology, Cluj Napoca, Romania Nuclear chromatin is a dynamic structure made of arrays of nucleosomes with different sizes and degrees of compaction. Structural rearrangements in chromatin rely on inter and intra nucleosome dynamics and are essential for gene regulation and cell fate transitions. Understanding these rearrangements requires elucidating nucleosome structural flexibility and how different factors affect it. In the nucleosome, 145-147 base pairs of DNA are wrapped around an octamer formed by four histone proteins. The histones have a structured core region and terminal disordered tails. Intra nucleosome dynamics in complete nucleosomes with genomic sequences are still poorly understood. Our recent data from a total of 25 µs atomistic molecular dynamics simulations revealed how the interplay of two histone tails mediate breathing motions of native nucleosomes by transient interactions with different DNA segments. Moreover, when the tails were removed, the DNA sequence determined the amplitude of nucleosome breathing. The nucleosomes we studied are bound by the transcription factor Oct4, a master regulator of stem cell pluripotency, during the conversion of somatic cells to pluripotent stem cells. Therefore, we further aimed to understand how the binding of Oct4 impacts intra nucleosome dynamics. From additional 30 µs of atomistic simulations and experiments, we found that Oct4 requires some nucleosome opening to bind at some locations on the nucleosome and stabilizes partially open nucleosome conformations. Under certain conditions defined by the binding site position and the configuration of the histone tails, the binding of Oct4 induces a large opening of the nucleosome. This open conformation is stable after Oct4 removal for at least 2 µs. The closing of the nucleosome in the presence and absence of Oct4 depends on how fast the interactions between the histone tails and the linker DNA are re-established.

40