Biomolecular Condensates Through a Computational Microscope Design, Mechanisms and Implications

Abstract

Biomolecular condensates, ubiquitous in biology, are crucial in organizing cellular functions and regulating various biochemical processes. In this thesis, I explore the emergent behaviours of these biomolecular systems via computational simulations and biophysical insights. I quantify and describe the key role of molecular interactions and structural properties in dictating phase separation, stability, and large-scale organization. Finally, I demonstrate that mean-field, coarse-grained computational models are powerful predictive tools for capturing the complex dynamics of a myriad of biomolecular condensates, providing insights into how basic molecular forces such as electrostatics, cation-$\uppi$ and $\uppi$-$\uppi$ stacking are sufficient to drive phase separation in diverse systems. My findings show that valency is a master regulator of phase separation, influencing both the propensity for condensate formation and the material properties of the resulting coaservates. By examining prion-like domains, I show how specific residue identities modulate the phase behaviour by altering the interaction landscape. Similarly, in CTPR-based constructs and chromatin arrays, valency also emerges as a key determinant of stability, linking molecular-scale interactions to macroscopic properties. This study highlights the critical role of structural and mechanical properties in modulating large-scale organization of biomolecular systems. Indeed, the multiscale approach taken demonstrates that the interplay between valency, molecular interactions and structure is essential for understanding the principles governing phase separation and chromatin organization. I argue that studying complex, emergent behaviours such as biomolecular phase separation requires a fully integrated interdisciplinary approach that combines biophysics, structural biology and computational chemistry. This thesis remarks on the need to move beyond simplified models for computational simulations and integrate experimental measurements with advanced simulations to accurately predict, understand, and design biomolecular behaviour. My research, grounded in bottom-up computational approaches, provides a framework for the rational design of biomolecular condensates with tailored properties, offering new insights into the mechanisms of cellular organization and potential therapeutic applications targeting aberrant phase separation in diseases.