Organic phases in cells: Elucidating the physical nature of biological liquid droplets

ongoing

Recently it has emerged that ‘membraneless organelles’ a commonly encountered body for compartmentalisation in Eukaryotic cells that include ‘nucleoli’ and ‘stress granules’, are phase separated liquid droplets suspended inside cells, formed from highly mobile disordered proteins. My research has focused on the prediction from physical theory, that the interior of liquid droplets should have very different chemical properties to the exterior dilute phase. By quantitatively analysing model biological liquid droplets formed by the Ddx4N1 protein, we discovered that their interior resembles an organic solvent (DMSO), can melt double stranded DNA, and selects which proteins can enter based on a simple sequence-based algorithm, akin to a chemical solubility rule. The field of biological liquid droplets has largely focused on phenomenological observations. This proposal aims to step beyond this and test the central hypothesis that “intermolecular interactions drive biological liquid droplet formation to create regions of solvent tailored to promote specific chemical functions”. By studying a diverse range of biological liquid droplets, I seek to establish that physico-chemical properties explain both when liquid droplets mix and when they do not, explain which molecules are absorbed and which are not, use these features to predict new properties to design new functionalised sequences using rules based on their fundamental inter-molecular interactions, determine structures of the liquid droplets using NMR and cryo-electron tomography and investigate the effects of liquid droplets on chemical reactivity. This research has the potential to change our understanding of the mechanisms of biochemistry, and use principles from physical chemistry to explain why cells naturally create these regions of effectively organic solvent inside the cell as part of their life cycle.