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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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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.
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pcbi-1003990-g001: 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.

Mentions: A schematic view of our CG protein and DNA model is shown in Fig. 1. Many DNA binding proteins form homo dimers, where the dimeric proteins have two DNA binding domains, e.g. lactose repressor, tryptophan repressor, λ repressor, etc. [26]. In this work, a protein molecule is represented by three beads: one representing a protein body portion, named the “PBP” bead, and the rest of the beads represent the DNA binding portion, named “DBP”, which have positive charges to bind to DNA. For the DNA molecule, the two adjacent nucleotides in the double strand are represented by a pseudo phosphate “PP” bead at the position of the phosphate atom in one strand of the canonical B-form of DNA. Since the bead represents two adjacent nucleotides, we set the effective charge of the PP beads to be −2. PP beads are connected to pseudo backbone “PB” beads, located on the long axis of the DNA. Radii, σ, for excluded volume effects explained below, Stokes radii, a, and effective charges, q, of the beads are listed in Table 1. σ values were determined to represent geometrical features of DNA. The distance between adjacent phosphate atoms is about 12.6 Å in B-DNA, with two adjacent nucleotides represented by one PP bead. To reproduce the excluded volume of the two adjacent nucleotides, the radii of the PP beads were set to 10.4 Å. The center of PBP was placed at 38 Å which gives an off-axis distance of 47 Å ( = 9+38) between Roc values of LacI (55 Å) and hOgg1 (25 Å) as reported in Ref. [17]. The radii of the PBP were set to 27.6 Å ( = 38–10.4 Å). DBP's radii of 6 Å were used to geometrically fit between PP beads. This is slightly smaller than the surface distance between PP beads, 7 Å. The assigned a for beads of CG-DNA give translational diffusion coefficients of small DNA fragments (8 bp to 24 bp) close to the experimental values [27].


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)

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.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003990-g001: 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.
Mentions: A schematic view of our CG protein and DNA model is shown in Fig. 1. Many DNA binding proteins form homo dimers, where the dimeric proteins have two DNA binding domains, e.g. lactose repressor, tryptophan repressor, λ repressor, etc. [26]. In this work, a protein molecule is represented by three beads: one representing a protein body portion, named the “PBP” bead, and the rest of the beads represent the DNA binding portion, named “DBP”, which have positive charges to bind to DNA. For the DNA molecule, the two adjacent nucleotides in the double strand are represented by a pseudo phosphate “PP” bead at the position of the phosphate atom in one strand of the canonical B-form of DNA. Since the bead represents two adjacent nucleotides, we set the effective charge of the PP beads to be −2. PP beads are connected to pseudo backbone “PB” beads, located on the long axis of the DNA. Radii, σ, for excluded volume effects explained below, Stokes radii, a, and effective charges, q, of the beads are listed in Table 1. σ values were determined to represent geometrical features of DNA. The distance between adjacent phosphate atoms is about 12.6 Å in B-DNA, with two adjacent nucleotides represented by one PP bead. To reproduce the excluded volume of the two adjacent nucleotides, the radii of the PP beads were set to 10.4 Å. The center of PBP was placed at 38 Å which gives an off-axis distance of 47 Å ( = 9+38) between Roc values of LacI (55 Å) and hOgg1 (25 Å) as reported in Ref. [17]. The radii of the PBP were set to 27.6 Å ( = 38–10.4 Å). DBP's radii of 6 Å were used to geometrically fit between PP beads. This is slightly smaller than the surface distance between PP beads, 7 Å. The assigned a for beads of CG-DNA give translational diffusion coefficients of small DNA fragments (8 bp to 24 bp) close to the experimental values [27].

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