Effect of neutral crowders on alpha-synuclein aggregation kinetics using scaled SOP-IDP model

There is a need for a computationally efficient theoretical model to study condensate formation by IDPs under various cellular conditions. Herein, we introduce a scaled Self-Organized Polymer–Intrinsically Disordered Protein (SOP-IDP) coarse-grain model that can explain the condensate formation of the FUS-LCD and alpha synuclein. The model is found to give robust results for both these systems. We applied this model to study the condensate formation of alpha-synuclein in the presence of differently sized neutral crowders. The simulation lag time observed relates to the experimental trend. Our studies give insight into how crowders can modulate the condensate formation. It is found that when the crowder size is smaller than the protein radius of gyration (R g ), ineffective collisions dominate at higher crowder concentration. In contrast, volume-exclusion effect becomes more significant when intermediate-sized crowders are present. Larger crowders trap protein oligomers within their voids, thereby inhibiting further growth. These crowders at higher crowder concentrations can impede the overall aggregation rate and limit aggregate size. The comprehensive result of the ineffective collisions and volume exclusion effect promotes the formation of the LLPS state at an optimum crowder concentration (5-10 % in the current simulation studies). The excess transfer free energy was found to be minimum at intermediate crowder concentration (5-10 % w/v). Our simulations provide a plausible explanation for the formation of a stable droplet at the optimum concentration (∼10 % w/v) of neutral crowders, as seen by most experimental groups.