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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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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.
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pcbi-1003990-g002: 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.

Mentions: Binding affinities for non-specific DNA binding for several proteins have been estimated to be in the range of 10 kBT (5.9 kcal/mol) to 15 kBT (8.9 kcal/mol) at physiological salt concentrations [37]. We employed the umbrella sampling technique to estimate the binding affinities of the CG model with various charges of the DBP beads, q(DBP). In Fig. 2, binding free energies as a function of q(DBP) are shown. CG-proteins with q(DBP) = 8–10 with restrained CG-DNA have a binding free energy of 5.71±0.02 to 9.00±0.02 kcal/mol, which is close to the experimental estimate. For the flexible CG-DNA model, fluctuation of the CG-DNA reduces binding affinity; here CG-proteins with q(DBP) = 8 to 15 have binding free energies within the range of experimental estimates.


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003990-g002: 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.
Mentions: Binding affinities for non-specific DNA binding for several proteins have been estimated to be in the range of 10 kBT (5.9 kcal/mol) to 15 kBT (8.9 kcal/mol) at physiological salt concentrations [37]. We employed the umbrella sampling technique to estimate the binding affinities of the CG model with various charges of the DBP beads, q(DBP). In Fig. 2, binding free energies as a function of q(DBP) are shown. CG-proteins with q(DBP) = 8–10 with restrained CG-DNA have a binding free energy of 5.71±0.02 to 9.00±0.02 kcal/mol, which is close to the experimental estimate. For the flexible CG-DNA model, fluctuation of the CG-DNA reduces binding affinity; here CG-proteins with q(DBP) = 8 to 15 have binding free energies within the range of experimental estimates.

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