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

Ando T, Skolnick J - PLoS Comput. Biol. (2014)

Bottom Line: Recent experimental results and theoretical analyses revealed that the proteins show a rotation-coupled sliding along DNA helical pitch.Our results indicate that intermolecular hydrodynamic interactions reduce 1D diffusivity by 30%.This hopping significantly increases sliding speed.

View Article: PubMed Central - PubMed

Affiliation: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

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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Related in: MedlinePlus

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.
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pcbi-1003990-g004: 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.

Mentions: Finally, the effects of charge q(DBP) on 1D sliding rate are examined. In Fig. 4, representative trajectories in Z position of the model CG-proteins with various q(DBP) and a(PBP) = 40 Å are shown, where the restrained CG-DNA molecules were used. During 25 µs BD simulations, the CG-protein with q(DBP) of 7 to 10 hopped along the CG-DNA molecule (see Movie S3 that shows hopping of the CG-protein). This hopping is prominent for smaller q(DBP) values. This trend was not changed for the simulations with the flexible CG-DNA model. Apparent 1D diffusion coefficients of the CG-protein with a(PBP) = 40 Å and various q(DBP) with the restrained and flexible CG-DNA in the presence and absence of inter-HI are shown in Fig. 5. The CG-proteins with smaller q(DBP) values (<10) tend to slide quickly due to hopping for both CG-DNA models. For q(DBP)>10, D1D reached the same lower bound for both CG-DNA models. CG-proteins with q(DBP) = 8 to 10 have binding affinities within experimental estimates of non-specific DNA binding. Those proteins in our model showed hopping along DNA. Direct observations of the hopping by single molecule experiments are currently very difficult due to the limited experimental resolution. Our simulation supports the possibility of hopping for non-specifically DNA bounded proteins initially envisioned in the theory.


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

Ando T, Skolnick J - PLoS Comput. Biol. (2014)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263358&req=5

pcbi-1003990-g004: 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.
Mentions: Finally, the effects of charge q(DBP) on 1D sliding rate are examined. In Fig. 4, representative trajectories in Z position of the model CG-proteins with various q(DBP) and a(PBP) = 40 Å are shown, where the restrained CG-DNA molecules were used. During 25 µs BD simulations, the CG-protein with q(DBP) of 7 to 10 hopped along the CG-DNA molecule (see Movie S3 that shows hopping of the CG-protein). This hopping is prominent for smaller q(DBP) values. This trend was not changed for the simulations with the flexible CG-DNA model. Apparent 1D diffusion coefficients of the CG-protein with a(PBP) = 40 Å and various q(DBP) with the restrained and flexible CG-DNA in the presence and absence of inter-HI are shown in Fig. 5. The CG-proteins with smaller q(DBP) values (<10) tend to slide quickly due to hopping for both CG-DNA models. For q(DBP)>10, D1D reached the same lower bound for both CG-DNA models. CG-proteins with q(DBP) = 8 to 10 have binding affinities within experimental estimates of non-specific DNA binding. Those proteins in our model showed hopping along DNA. Direct observations of the hopping by single molecule experiments are currently very difficult due to the limited experimental resolution. Our simulation supports the possibility of hopping for non-specifically DNA bounded proteins initially envisioned in the theory.

Bottom Line: Recent experimental results and theoretical analyses revealed that the proteins show a rotation-coupled sliding along DNA helical pitch.Our results indicate that intermolecular hydrodynamic interactions reduce 1D diffusivity by 30%.This hopping significantly increases sliding speed.

View Article: PubMed Central - PubMed

Affiliation: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

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.

Show MeSH
Related in: MedlinePlus