Life in a Crowd: Macromolecular Crowding and Confinement Effects on Protein Interactions in Living Systems

Biological polymers carry out their functions in living systems where the environment is very concentrated or crowded by macromolecules. Physically, the composition of a cell is more than ``a sack of water''; its consistency is closer to Jell-O. Experiments suggests that, because of this macromolecular crowding effect that confines polymeric dynamics, the kinetics and thermodynamics of protein folding and the association rate constants of protein-protein interactions in a cell (in vivo) are very different from that ina diluted test tube (in vitro). In order to quantitatively understand macromolecular crowding and confinement effects on protein dynamics, we used coarse-grained models that physically captured interactions between crowders and a protein. The folding rates of a model protein nonmonotonically increased with the volume fraction of the crowders. At lower volume fractions, depletion-induced attractions from crowders could be mapped according to the spherical confinement model. A result of spherical confinement was the destabilization of denatured states by disallowing extended configurations that were longer than the pore size. However, at higher volume fractions, conformational fluctuations of a protein were susceptible to the shape of the confining condition. Thus, an approximation of the spherical confinement to mimic crowding effects was no longer effective.