Self-crowding induced phase separation in protein dispersions

The coupling between protein conformation, molecular volume, and solution phase behaviour is studied theoretically for a two-state, coarse-grained protein model in which protein molecules can reversibly switch between a native and a non-native excited state. In the model, native and non-native conformers are represented by perfect spheres with different hard-core diameters. We presume the larger, non-native species to attract each other through some unspecified potential. We find that at low concentrations the native state is stabilised energetically and that at high concentrations the native state is again stabilised but this time by self-crowding, i.e., a lack of free volume. These two regimes are separated by two first-order transitions from a region where the non-native conformational state is prevalent, stabilised by attractive interactions between the proteins. The calculated phase diagram is very sensitive to even quite small differences in particle volumes and has unusual features, including the loss of a critical point if the size difference is sufficiently large.