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. 2014 Dec 11;10(12):e1003990.
doi: 10.1371/journal.pcbi.1003990. eCollection 2014 Dec.

Sliding of proteins non-specifically bound to DNA: Brownian dynamics studies with coarse-grained protein and DNA models

Tadashi Ando  1 , Jeffrey Skolnick  1
Affiliations

Sliding of proteins non-specifically bound to DNA: Brownian dynamics studies with coarse-grained protein and DNA models

Tadashi Ando et al. PLoS Comput Biol. .

Abstract

DNA binding proteins efficiently search for their cognitive sites on long genomic DNA by combining 3D diffusion and 1D diffusion (sliding) along the DNA. Recent experimental results and theoretical analyses revealed that the proteins show a rotation-coupled sliding along DNA helical pitch. Here, we performed Brownian dynamics simulations using newly developed coarse-grained protein and DNA models for evaluating how hydrodynamic interactions between the protein and DNA molecules, binding affinity of the protein to DNA, and DNA fluctuations affect the one dimensional diffusion of the protein on the DNA. Our results indicate that intermolecular hydrodynamic interactions reduce 1D diffusivity by 30%. On the other hand, structural fluctuations of DNA give rise to steric collisions between the CG-proteins and DNA, resulting in faster 1D sliding of the protein. Proteins with low binding affinities consistent with experimental estimates of non-specific DNA binding show hopping along the CG-DNA. This hopping significantly increases sliding speed. These simulation studies provide additional insights into the mechanism of how DNA binding proteins find their target sites on the genome.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Schematic view of the CG-protein and CG-DNA models.
PBP and DBP represent a Protein Body Portion and a DNA Binding Portion of the CG-protein model, respectively. PP and PB represent a Pseudo Phosphate of two adjacent nucleotides and a Pseudo Backbone of double strand DNA, respectively. PBP and DBP beads are connected to each other by a harmonic potential, represented as a black line. The excluded volume radii for each bead used in the simulations are shown.
Figure 2
Figure 2. Binding free energy estimated by the umbrella sampling method for various charge values of DBP beads, q(DBP), in the CG-protein model with the restrained and flexible CG-DNA models.
Stokes radius of the PBP bead, a(PBP), of 40 Å was used for this estimation.
Figure 3
Figure 3. Representative trajectories of X, Y, and Z positions of the PBP bead in the CG-protein molecules with a(PBP) of 40 Å and q(DBP) of 20.
The BD simulation was done in the absence of intermolecular HI and all beads of the CG-DNA molecule were restrained by a harmonic potential.
Figure 4
Figure 4. Representative trajectories of z position of the PBP bead in the CG-protein molecules with a(PBP) of 40 Å and q(DBP) of 7, 8, 9, 10, 15, and 20.
BD simulations shown in this figure were done in the absence of intermolecular HI using the same random seed. Arrows indicate times that hopping was observed.
Figure 5
Figure 5. Apparent 1D diffusion coefficients of the CG-protein molecules with a(DBP) = 40 and q(DBP) = 5, 6, 7, 8, 9, 10, 15, and 20 obtained from the BD simulations (left) with the restrained CG-DNA and (right) with the flexible CG-DNA models in the presence and absence of intermolecular HI.
These values are average over ten BD simulations.
See this image and copyright information in PMC

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