Modeling molecular interactions to understand spatial crowding effects on heterodimer formations

Molecular crowding occurs when the density of interacting molecules in some reaction system is sufficient to create deviations from traditional mass-action models of chemistry in diffusive systems. While there is a great deal of theory on the influence of molecular crowding on biochemistry in vivo, the effects are highly dependent on specific assumptions about the shapes, volumes, and diffusion properties of the components of an individual system and are thus difficult to predict from first principles. In this study, we use lattice Monte Carlo simulations to examine the effects on a reaction system for two limiting cases of the diffusion behavior of inert crowding agents. In cells, inert molecules might diffuse throughout a solute along with the reactant species by passive diffusion or may be anchored at fixed positions within the solute. We investigate the relative contributions of the two models to crowding effects by examining moving inert particles versus stationery inert particles on the kinetics of a heterodimer assembly system. The two models of inert crowding agents resulted in highly divergent effects on the reactant system. Stationary particles exhibited a bimodal response in the reaction rate curve that was a function of copy number and spatial arrangement and which accelerated the process at conditions not unlike those found in cellular environments. On the other hand, moving inert particles created a well mixed background that had no effect on the reaction process even under extremely compacted conditions. These results may have applications in developing more realistic simulations of reaction chemistry in crowded environments such as living cells.