Crosslink-Induced Conformation Change of Intrinsically Disordered Proteins Have a Nontrivial Effect on Phase Separation Dynamics and Thermodynamics.

Biomolecule condensates formed via liquid-liquid phase separation (LLPS) play crucial roles within various cellular processes. Despite numerous theoretical and experimental discoveries, the general principle by which the protein conformation affects the propensity for LLPS remains poorly understood. Here, we systematically address this issue using a general coarse-grained model of intrinsically disordered proteins (IDPs) with different degrees of intrachain crosslinks. We find that an increased conformation collapse due to higher intrachain crosslink ratio enhances the thermodynamic stability of protein phase separation and found the critical temperature has a good scaling law with the proteins' average radius of gyration . Such correlation is robust regardless of interaction types and sequence patterns. Strikingly, the growth dynamics of the LLPS process, contrary to the thermodynamic observation, is generally more favored at proteins with extended conformation. Faster condensate growing speed is again observed for higher- collapsed IDPs, resulting altogether in a nonmonotonic dynamics as a function of . A phenomenological understanding of the phase behavior is provided by a mean-field model with an effective Flory interaction parameter χ, which is found to have a good scaling law with conformation expansion. Our study shed lights on the general mechanism for understanding and modulation of phase separation with different conformation profiles and may provide new evidence in reconciling the contradictions in thermodynamic- and dynamic-controlled experimental LLPS observations.