Biophysical Society Thematic Meeting| Les Houches 2019

Multiscale Modeling of Chromatin: Bridging Experiment with Theory

Monday Speaker Abstracts

INTEGRATING IN SILICO AND IN VITRO APPROACHES TO CHARACTERIZE NUCLEOSOME STRUCTURE AND DYNAMICS WITH HIGH PRECISION Anna Panchenko 1 ; 1 National Institutes of Health, NCBI, Bethesda, Maryland, United States At the heart of the interplay between protection and accessibility of the genetic material lies the nucleosome. Nucleosomes experience a broad repertoire of alterations that affect their structure, dynamics, and interactions with various chromatin binding partners. We use hydroxyl-radical footprinting, chemical crosslinking and molecular modeling to explore conformational polymorphism of nucleosomes both at local and global scales. Such an integrative approach enables insights into the functionally relevant motions in nucleosomes including coupling between conformations of histone tails and DNA geometry, the rearrangements in histone core and histone-DNA interactions, with important implications for binding of chromatin remodelers and nucleosome translocation. In addition, our methods allow to produce high resolution atomistic structural models of different variant nucleosomes refined by experimental data. Specific binding interfaces of variant nucleosomes have been identified that are composed of nuclesomal DNA and histone fold regions pointing to key molecular recognition features. STRUCTURAL PLASTICITY OF HISTONE OLIGOMERS AND THEIR INTERACTIONS WITH CHAPERONES AND OTHER REGULATORS Garegin A. Papoian 1 ; 1 The University of Maryland, Chemistry and Biochemistry, IPST, College Park, Maryland, United States To gain deeper insights into the nucleosomal particle, it is useful to deconstruct the histone octameric core into the constituent tetramer and two dimers. Towards achieving this goal, we used atomistic and coarse-grained simulations to investigate various histone oligomers, from dimers to the histone octamer in the nucleosome, and also subsequent complex formation with histone chaperones and other proteins regulating chromatin. We studied both canonical histones, as well as a centromeric histone H3 variant, CENP-A, finding that despite nearly identical structures, CENP-A nucleosomes are significantly more distortable and dynamic. We further traced this difference to the structural frustration or incompatibility between the preferred CENP- A/H4 tetramer structure and the corresponding octamer structure in the nucleosome. Furthermore, we found that various histone chaperones and binding partners, such as CENP-C, can rigidify the nucleosome in a switch-like fashion. In a separate line of work, we used coarse- grained simulations to study how the H1 linker histone interacts with nucleosomal DNA and other histones, regulating the distribution of nucleosomal conformations.

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