Project Summary
The formation of biomolecular condensates through phase separation is emerging as an
important mechanism for cellular organization and function. The frequent observation of these
condensates at sites of DNA damage, during stress response, and as a precursor to
pathological aggregates in vivo has generated significant interest in their potential roles in
cellular function. However, the relationship between protein sequence and formation,
microstructural organization, and dynamics of biomolecular condensates is only beginning to be
probed. Our belief is that a synergistic combination of computer modeling integrated with
experimental techniques such as NMR, microscopy, and microrheology, to name a few, can
provide the best path toward uncovering the underlying relationship between amino acid
sequence and phase separation. Our strategy to elucidate the molecular origins of phase
separation in biology involves utilizing innovative models and methods developed by us in close
collaboration with leading experimentalists to reconstitute biologically relevant phase separation
systems in silico, thereby translating our extensive knowledge of the molecular determinants of
phase separation of proteins, to biologically relevant processes. Our proposed future work aims
to develop and utilize multiscale computational methods from the atomic to the mesoscale level
to build a molecular mechanistic framework for the predictive modeling of phase separation in
essential biological processes. Our efforts will focus on two biological problems of significant
interest. The first part of the project will focus on the phase separation of RNA binding proteins
and their role in DNA damage repair and transcriptional condensates formed by fusion
oncoproteins. The second part of the project will aim to provide a detailed molecular picture of
phase separated protein assemblies in chromatin organization as it pertains to the co-phase
separation of heterochromatin protein 1 (HP1) family with other chromatin-associated proteins
and satellite RNA in constitutive heterochromatin formation, HP1 proteins in gene expression
and cancer drug resistance, and the role of phase separation of polyhomeotic protein (PhP) in
chromatin regulation. These approaches will generate detailed molecular-level information on
the assembly of many components into heterochromatin assemblies and provide the
background knowledge needed to better understand its regulation and disease relevance.