Optimal Resolution to Model Protein Crowding Effects: Lessons from GB1 Dimerization

Abstract

Biochemical reactions occur in a heterogeneous and crowded environment. Computer simulations are useful tools to obtain mechanistic insights into crowder induced changes to the reaction. However, from a simulation perspective, it is important to decipher the level of structural resolution in a protein-crowder model that can faithfully capture the influences of crowding on protein association with limited computational resources. Here, we investigate the dimerization of model system GB1 in the presence of lysozyme crowders at two structural resolutions. The lower resolution model assumes both protein and crowder species as spherical beads, similar to the analytical scaled particle theory model, whereas the higher resolution model retains residue specific structural details for protein and crowder species. From the higher resolution model, it is found that GB1 dimer formation is destabilized in the presence of lysozyme crowders, and the destabilization is more for the sideby-side dimer compared to the domain-swapped dimer, in qualitative agreement with experimental findings. However, the low resolution CG model predicts stabilization of the dimers in the presence of the lysozyme crowder, similar to the SPT model. These results indicate a nontrivial role of the choice of model resolution in computer simulation studies investigating crowder induced effects.