Abstract
The effect of macromolecular crowding on diffusion beyond the hard-core sphere model is studied. A new coarse-grained model is presented, the Chain Entanglement Softened Potential (CESP) model, which takes into account the macromolecular flexibility and chain entanglement. The CESP model uses a shoulder-shaped interaction potential that is implemented in the Brownian Dynamics (BD) computations. The interaction potential contains only one parameter associated with the chain entanglement energetic cost (Ur). The hydrodynamic interactions are included in the BD computations via Tokuyama mean-field equations. The model is used to analyze the diffusion of a streptavidin protein among different sized dextran obstacles. For this system, Ur is obtained by fitting the streptavidin experimental long-time diffusion coefficient Dlongversus the macromolecular concentration for D50 (indicating their molecular weight in kg mol-1) dextran obstacles. The obtained Dlong values show better quantitative agreement with experiments than those obtained with hard-core spheres. Moreover, once parametrized, the CESP model is also able to quantitatively predict Dlong and the anomalous exponent (α) for streptavidin diffusion among D10, D400 and D700 dextran obstacles. Dlong, the short-time diffusion coefficient (Dshort) and α are obtained from the BD simulations by using a new empirical expression, able to describe the full temporal evolution of the diffusion coefficient.
Highlights
Biological media are known to contain a high concentration of a wide variety of macromolecular species such as proteins, polysaccharides or nucleic acids
In all the Brownian Dynamics (BD) computations performed in the rest of this work, unique parameter (Ur) has been set to this value, which indicates that, for dextran, the repulsion forces arising from chain entanglement slightly dominate over the attractive ones
A new coarse grained approach to macromolecular diffusion in crowded media that goes beyond the hard sphere model is presented: the Chain Entanglement Softened Potential (CESP) model
Summary
Biological media are known to contain a high concentration of a wide variety of macromolecular species such as proteins, polysaccharides or nucleic acids. The weight fraction of protein is around 5% in lymph, 9% in blood plasma and 35% in hemolysate.[1,2] In the cellular cytosol, three-dimensional analysis of electron micrographs revealed a 20% volume fraction of fibrous supramolecular structures (i.e. F-actin, microtubules and intermediate filaments).[3] These conditions, known as ‘‘macromolecular crowding’’ involve non-specific interactions among macromolecular species due to the excluded volume, van der Waals, electrostatic and hydrodynamic interactions. The comparison of the computational results with the experimentally observed results facilitates the quantification of the factors governing macromolecular diffusion in crowded media. Different computational approaches have been applied ranging from on-lattice Monte Carlo simulations[16,17] and off-lattice Brownian Dynamics (BD)[18,19,20,21,22,23,24,25] to Molecular Dynamics simulations.[23,26,27] In implicit solvent simulations like BD, the Hydrodynamic Interactions (HIs) of the macromolecules have been found to be crucial to properly describe their motion in crowded media.[28]
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