Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Tuesday Speaker Abstracts

MOLECULAR RECOGNITION BY PHASE-SEPARATED CONDENSATES IN SMALL RNA BIOLOGY Kumar Gaurav 1,2 ; Lukas Stelzl 1,2 ; 1 Institute of Molecular Biology, Mainz, Germany

2 Institute of Physics, Mainz, Germany 3 Faculty of Biology, Mainz, Germany

Trans-generational epigenetic inheritance (TEI) is the transmission of epigenetic information across generations via small RNAs or proteins present in the sperm or eggs. In many organisms including humans, small RNAs play an essential role in TEI. In C. elegans, TEI is facilitated by a small RNA. Small RNA-based molecular mechanisms are often choreographed in non- membraneous organelles called bio-molecular condensates. The formation of these condensates is orchestrated by the liquid-liquid phase separation of the proteins containing intrinsically disordered regions (IDR) or by multivalent proteins. Experiments have shown that PEI granules need to specifically recognise their native binding partners to mediate TEI and ensure that correct RNAs are inherited. To understand how PEI granules achieve their biological function by specific molecular recognition we are studying PEI granules and their biological patterns with multi-scale simulations. Coarse-grained simulations with implicit solvent enabled us to investigate the co-phase separation of PEI-granules proteins and their binding partners and thus the possible roles of inherent sequence-encoded affinities for the recognition of disordered proteins by phase-separated PEI-granules. In these simulations, we explored the possible roles of post-translational modifications such as phosphorylation and proteolytic cleavage on modulating the recognition by PEI granules. To better understand the molecular driving forces of PEI granule phase behaviour and molecular recognition by these granules we employ large-scale coarse-grained simulations (> 1 Million particles and hundreds of proteins) with near-atomic resolution and explicit solvent. Back-mapping to atomistic representations and simulations of sub-systems will enable us to ultimately understand with an atomic resolution how PEI granules ensure TEI of the correct RNAs.

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