Proteins can form droplets via liquid–liquid phase separation (LLPS) in cells. Recent experiments demonstrate that LLPS is qualitatively different on two-dimensional (2D) surfaces compared to three-dimensional (3D) solutions. In this paper, we use mathematical modeling to investigate the causes of the discrepancies between LLPS in 2D and 3D. We model the number of proteins and droplets inducing LLPS by continuous-time Markov chains and use chemical reaction network theory to analyze the model. To reflect the influence of space dimension, droplet formation and dissociation rates are determined using the first hitting times of diffusing proteins. We first show that our stochastic model reproduces the appropriate phase diagram and is consistent with the relevant thermodynamic constraints. After further analyzing the model, we find that it predicts that the space dimension induces qualitatively different features of LLPS, which are consistent with recent experiments. While it has been claimed that the differences between 2D and 3D LLPS stem mainly from different diffusion coefficients, our analysis is independent of the diffusion coefficients of the proteins since we use the stationary model behavior. Our results thus give new hypotheses about how space dimension affects LLPS.
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