Biochemical reactions in crowded environments: revisiting the effects of volume exclusion with simulations

Gomez, David; Klumpp, Stefan

doi:10.3389/fphy.2015.00045

Cited by 31 publications

(39 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apart from the RDME lattice models, there is another class of schemes, which we refer as microscopic lattice method (MLM) that represents molecules at single particle resolution [39][40][41][42][43][44][45][46][47][48][49][50]. In most of these schemes [39, 41-45, 47, 50], the size of the voxel follows the molecule size, whereas in the small-voxel tracking algorithm (SVTA) [48], a particle can occupy multiple voxels, providing greater spatial resolution at the cost of higher computational complexity.…”

Section: Introductionmentioning

confidence: 99%

Reaction-diffusion kinetics on lattice at the microscopic scale

et al. 2018

View full text Add to dashboard Cite

Lattice-based stochastic simulators are commonly used to study biological reaction-diffusion processes. Some of these schemes that are based on the reaction-diffusion master equation (RDME), can simulate for extended spatial and temporal scales but cannot directly account for the microscopic effects in the cell such as volume exclusion and diffusion-influenced reactions. Nonetheless, schemes based on the high-resolution microscopic lattice method (MLM) can directly simulate these effects by representing each finite-sized molecule explicitly as a random walker on fine lattice voxels. The theory and consistency of MLM in simulating diffusion-influenced reactions have not been clarified in detail. Here, we examine MLM in solving diffusion-influenced reactions in 3D space by employing the Spatiocyte simulation scheme. Applying the random walk theory, we construct the general theoretical framework underlying the method and obtain analytical expressions for the total rebinding probability and the effective reaction rate. By matching Collins-Kimball and lattice-based rate constants, we obtained the exact expressions to determine the reaction acceptance probability and voxel size. We found that the size of voxel should be about 2% larger than the molecule. The theoretical framework of MLM is validated by numerical simulations, showing good agreement with the off-lattice particle-based method, eGFRD. MLM run time is more than an order of magnitude faster than eGFRD when diffusing macromolecules with typical concentrations observed in the cell. MLM also showed good agreements with eGFRD and mean-field models in case studies of two basic motifs of intracellular signaling, the protein production-degradation process and the dual phosphorylation-dephosphorylation cycle. In addition, when a reaction compartment is populated with volume-excluding obstacles, MLM captures the non-classical reaction kinetics caused by anomalous diffusion of reacting molecules.

show abstract

Section: Introductionmentioning

confidence: 99%

Reaction-diffusion kinetics on lattice at the microscopic scale

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In addition, computational studies have been performed in order to understand the effect of macromolecular crowding [8]. These studies use different approaches such as on-lattice Monte Carlo simulations [9] or off-lattice Brownian Dynamics (BD) simulations [10,11]. Recently, macromolecular crowding effect on diffusion has been modelled by means of atomistic models of cytoplasm using Molecular Dynamics [12].…”

Section: Introductionmentioning

confidence: 99%

Brownian Dynamics Computational Model of Protein Diffusion in Crowded Media with Dextran Macromolecules as Obstacles

Blanco

Via

Garcés

et al. 2017

Entropy

View full text Add to dashboard Cite

The high concentration of macromolecules (i.e., macromolecular crowding) in cellular environments leads to large quantitative effects on the dynamic and equilibrium biological properties. These effects have been experimentally studied using inert macromolecules to mimic a realistic cellular medium. In this paper, two different experimental in vitro systems of diffusing proteins which use dextran macromolecules as obstacles are computationally analyzed. A new model for dextran macromolecules based on effective radii accounting for macromolecular compression induced by crowding is proposed. The obtained results for the diffusion coefficient and the anomalous diffusion exponent exhibit good qualitative and generally good quantitative agreement with experiments. Volume fraction and hydrodynamic interactions are found to be crucial to describe the diffusion coefficient decrease in crowded media. However, no significant influence of the hydrodynamic interactions in the anomalous diffusion exponent is found.

show abstract

“…The traditional theory of macromolecular crowding predicts that protein-ligand and protein-protein interactions in crowded environments would be stronger than those in dilute solution. The volume exclusion effect has been considered as a main driving force 21,58 . This effect suggests an increase of the effective concentration of the substrates around the target macromolecule.…”

Section: Discussionmentioning

confidence: 99%

Reduced Efficacy of a Src Kinase Inhibitor in Crowded Protein Solution

Kasahara

Nawrocki

et al. 2020

Preprint

View full text Add to dashboard Cite

The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, PP1, in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. Protein functions in a living cell could be examined using atomistic MD simulations with realistic cellular environments.

show abstract

Biochemical reactions in crowded environments: revisiting the effects of volume exclusion with simulations

Cited by 31 publications

References 50 publications

Reaction-diffusion kinetics on lattice at the microscopic scale

Reaction-diffusion kinetics on lattice at the microscopic scale

Brownian Dynamics Computational Model of Protein Diffusion in Crowded Media with Dextran Macromolecules as Obstacles

Reduced Efficacy of a Src Kinase Inhibitor in Crowded Protein Solution

Contact Info

Product

Resources

About