Ridgway, D., Broderick, G., Lopez-Campistrous, A., Ru'aini, M., Winter, P., Hamilton, M., Boulanger, P., Kovalenko, A. and Ellison, M. J. (2008). "Coarse-grained molecular simulation of diffusion and reaction kinetics in a crowded virtual cytoplasm" Biophysical Journal, 10, 3748-3759.

We present a general-purpose model for biomolecular simulations at the molecular level that incorporates stochasticity, spatial dependence, and volume exclusion, using diffusing and reacting particles with physical dimensions. To validate the model, we first established the formal relationship between the microscopic model parameters (time-step, move length, and reaction probabilities) and the macroscopic coefficients for diffusion and reaction rate. We then compared simulation results with Smoluchowski theory for diffusion-limited irreversible reactions and the best available approximation for diffusion-influenced reversible reactions. To simulate the volumetric effects of a crowded intracellular environment, we created a virtual cytoplasm composed of a heterogeneous population of particles diffusing at rates appropriate to their size. The particle size distribution was estimated from the relative abundance, mass and stoichiometries of protein complexes using an experimentally derived proteome catalogue from E. coli K12. Simulated diffusion constants exhibited anomalous behaviour as a function of time and crowding. Although significant, the volumetric impact of crowding on diffusion cannot fully account for retarded protein mobility in vivo, suggesting that other biophysical factors are at play. The simulated effect of crowding on arnase:barstar dimerization, an experimentally characterized example of a bimolecular association reaction, reveals a biphasic time course, indicating that crowding exerts different effects over different time scales. These observations illustrate that quantitative realism in biosimulation will depend to some extent on meso-scale phenomena that are not currently well understood.

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