Capturing the influence of a crowded environment on protein GB1 dimerization at coarse-grained resolutions.

Abstract

In-cell protein-protein association, which is crucial in enzyme catalysis and polymerization, occurs in an environment that is highly heterogeneous and crowded. The crowder molecules exclude the reactant molecules from occupying certain regions of the cell, resulting in changes in the reaction thermodynamics and kinetics. Recent studies, both experiment and simulations, also revealed that the nature of interaction between crowder and protein species, in particular the soft interactions, plays an important role in crowder induced effects on protein association. To this end, 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. Here we investigate a model protein system in a dilute medium as well as in a crowded medium, adopting two structural resolutions of the constituent molecules, and using either molecular or Langevin dynamics to propagate the equations of motion. In particular, we look at dimerization of protein GB1, since GB1 dimers can exist in both side-by-side and domain-swapped conformations, showing the important role of residue-level structural details. The free energy change in protein association in a crowded solution relative to a crowder free medium obtained from the simulations is then compared with experimental results. The results reveal the pros and cons of adopting different resolution approaches.