Effect of mixed macromolecular crowding agents on protein folding

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Abstract
In cells, proteins fold and unfold in the presence of macromolecules with various sizes and shapes. Recent experiments by Liang and coworkers (J Biol Chem 2004;279:55109–55116; J Mol Biol 2006;364:469–482) show that protein refolding is enhanced by a mixture of two different crowding agents relative to the individual crowding agents and an optimal mixing ratio exists. Here, we present a theory that predicts the existence of an optimal mixing ratio. The theory is based on models for calculating the changes in the chemical potentials of the folded and unfolded states by a mixture of crowders. The existence of an optimal mixing ratio results from the dependences of these chemical‐potential changes on crowder sizes and concentrations, which can be argued to be quite general. We further predict that, for any crowding agent, the stabilizing effect can be optimized both by varying the molecular weight and the mixing ratio of two species with different molecular weights. Proteins 2008.