Biophysical Society Thematic Meeting| Les Houches 2019

Multiscale Modeling of Chromatin: Bridging Experiment with Theory

Poster Abstracts


Vinicius Fernandes 1,2 ; Kaian Teles 1 ; Camyla Ribeiro 1 ; Werner Treptow 2 ; Guilherme Santos 1 ; 1 University of Brasilia, Laboratory of Molecular Pharmacology, Department of Pharmacy, BrasÃlia, Distrito Federal, Brazil 2 University of Brasilia, Laboratory of Theoretical and Computational Biology, Department of Cell Biology, BrasÃlia, Distrito Federal, Brazil Structural changes in chromatin regulate gene expression and define phenotypic outcomes. Most recently, the formation of condensed chromatin regions based on phase-separation in the cell, a basic physical mechanism, was proposed. Increased understanding of the mechanisms of interaction between chromatin and lipids suggest that small lipid molecules, such as cholesterol and short-chain fatty acids, can regulate important nuclear functions. New biophysical and computational data has suggested that cholesterol interacts with nucleosome through multiple binding sites and affects chromatin structure in vitro. Regardless of the mechanism of how lipids bind to chromatin, there is currently little awareness that lipids may be stored in chromatin and influence its state. Recently, we review the main impacts of lipids on the nuclear environment, emphasizing its role on chromatin architecture. We postulate that lipids that bind to nucleosomes and affect chromatin states are likely to be worth investigating as tools to modify disease phenotypes at a molecular level. Focusing on lipids that bind to nuclear receptors, clinically relevant transcription factors, we are exploring the interactions of the nucleosome with steroid hormones, bile acids and fatty acids. Preliminary computational studies, employing molecular docking and all-atom molecular dynamics simulations, suggest that other lipid chemotypes may also impact chromatin structure through binding to common cholesterol sites on the nucleosome. For better charectization of lipids influence on chromatin, we are now investigating the effects of these chemotypes on a chromatin coarsed-grained model with the SIRAH force field. Despite preliminary, these observations suggests that lipid-chemotypes, may bind at common sites on the nucleosome surface. Still consistent with that notion is the fascinating possibility that via non- specific low-affinity interactions, chromatin may work as a lipid depot for nuclear proteins.


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