Effects of macromolecular crowding on biochemical reaction equilibria: a molecular thermodynamic perspective

Abstract

A molecular thermodynamic model is developed to investigate the effects of macromolecular crowding on biochemical reactions. Three types of reactions, representing protein folding/conformational isomerization, coagulation/coalescence, and polymerization/association, are considered. The reactants, products, and crowders are modeled as coarse-grained spherical particles or as polymer chains, interacting through hard-sphere interactions with or without nonbonded square-well interactions, and the effects of crowder size and chain length as well as product size are examined. The results predicted by this model are consistent with experimentally observed crowding effects based on preferential binding or preferential exclusion of the crowders. Although simple hard-core excluded-volume arguments do in general predict the qualitative aspects of the crowding effects, the results show that other intermolecular interactions can substantially alter the extent of enhancement or reduction of the equilibrium and can even change the direction of the shift. An advantage of the approach presented here is that competing reactions can be incorporated within the model.

FIGURE 1

Schematic illustration of a chemical reaction in the presence of crowder C. Although the reactant and the product are shown as spherical whereas the crowder is represented as a chainlike molecule, the theoretical formalism presented in the article allows each of them to be either spherical or chainlike.

FIGURE 2

Activity coefficient of reactant over that of product for folding as a function of the molar concentration of crowder C. Solid lines correspond to situations in which nonbonded SW interactions are included, whereas the dashed lines correspond to only the HS interactions. It has been assumed that and

FIGURE 3

Degree of reaction α for folding as a function of the molar concentration of crowder C. Solid lines correspond to situations in which nonbonded SW interactions are included, whereas the dashed lines correspond to only the HS interactions. For all the three cases shown below, it has been assumed that (a) The effect of the size of crowder: (b) The effect of the chain length of crowder: (c) The effect of the size of product:

FIGURE 4

Degree of reaction α for coagulation as a function of (a) molar concentration and (b) volume fraction of crowder C for the effect of the chain length of the crowder. Solid lines correspond to situations in which nonbonded SW interactions are included, whereas the dashed lines correspond to only the HS interactions. It has been assumed that and

FIGURE 5

Degree of reaction α for coagulation as a function of the molar concentration of crowder C. Solid lines correspond to situations in which nonbonded SW interactions are included, whereas the dashed lines correspond to only the HS interactions. For both cases shown below, it has been assumed that and (a) The effect of the size of crowder; (b) The effect of the size of product;

FIGURE 6

Degree of reaction α for polymerization as a function of (a) molar concentration and (b) volume fraction of crowder C for the effect of the chain length of the crowder. Solid lines correspond to situations in which nonbonded SW interactions are included, whereas the dashed lines correspond to only the HS interactions. It has been assumed that and

FIGURE 7

Degree of reaction α for polymerization as a function of the molar concentration of crowder C. Solid lines correspond to situations in which nonbonded SW interactions are included, whereas the dashed lines correspond to only the HS interactions. For both cases shown below, it has been assumed that and (a) The effect of the size of crowder; (b) The effect of the size of product;