Dominance Analysis: A formalism to uncover dominant energetic contributions to biomolecular condensate formation in multicomponent systems

Phase separation in aqueous solutions of macromolecules is thought to underlie the generation of biomolecular condensates in cells. Condensates are membraneless bodies, representing dense, macromolecule-rich phases that coexist with the dilute, macromolecule-deficient phase. In cells, condensates comprise hundreds of different macromolecular and small molecule solutes. Do all components contribute equally or very differently to the driving forces for phase separation? Currently, we lack a coherent formalism to answer this question, a gap we remedy in this work through the introduction of a formalism we term energy dominance analysis. This approach rests on model-free analysis of shapes of the dilute arms of phase boundaries, slopes of tie lines, and changes to dilute phase concentrations in response to perturbations of concentrations of different solutes. We present the formalism that underlies dominance analysis, and establish its accuracy and flexibility by deploying it to analyse phase spaces probed in silico, in vitro , and in cellulo . ### Competing Interest Statement The authors have declared no competing interest.