Limits...
DNA exit ramps are revealed in the binding landscapes obtained from simulations in helical coordinates.

Echeverria I, Papoian GA - PLoS Comput. Biol. (2015)

Bottom Line: The computed PMFs show that, even for small ligands, the free energy landscapes are complex.For example, we identified the presence of dissociation points or "exit ramps" that naturally would terminate sliding.We discuss how our findings have important implications for understanding how proteins and ligands associate and slide along DNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, United States of America; Institute for Physical Science and Technology, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
DNA molecules are highly charged semi-flexible polymers that are involved in a wide variety of dynamical processes such as transcription and replication. Characterizing the binding landscapes around DNA molecules is essential to understanding the energetics and kinetics of various biological processes. We present a curvilinear coordinate system that fully takes into account the helical symmetry of a DNA segment. The latter naturally allows to characterize the spatial organization and motions of ligands tracking the minor or major grooves, in a motion reminiscent of sliding. Using this approach, we performed umbrella sampling (US) molecular dynamics (MD) simulations to calculate the three-dimensional potentials of mean force (3D-PMFs) for a Na+ cation and for methyl guanidinium, an arginine analog. The computed PMFs show that, even for small ligands, the free energy landscapes are complex. In general, energy barriers of up to ~5 kcal/mol were measured for removing the ligands from the minor groove, and of ~1.5 kcal/mol for sliding along the minor groove. We shed light on the way the minor groove geometry, defined mainly by the DNA sequence, shapes the binding landscape around DNA, providing heterogeneous environments for recognition by various ligands. For example, we identified the presence of dissociation points or "exit ramps" that naturally would terminate sliding. We discuss how our findings have important implications for understanding how proteins and ligands associate and slide along DNA.

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Binding free-energy landscape for Na+ in the minor groove: The PMF was computed for one complete turn (2π) along the minor groove in the helical coordinates system (see S1 Fig.).The PMF was projected to the 2D plane, such that the ξ-axis is perpendicular to the page (see Methods sections and S1 Fig.) and the obtained free-energies are those of a “ribbon” passing through the middle of the minor groove’s sampled volume. In this representation the DNA’s axis is at the center of the plot. Note that in this coordinate system there is no angular periodicity.
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pcbi.1003980.g002: Binding free-energy landscape for Na+ in the minor groove: The PMF was computed for one complete turn (2π) along the minor groove in the helical coordinates system (see S1 Fig.).The PMF was projected to the 2D plane, such that the ξ-axis is perpendicular to the page (see Methods sections and S1 Fig.) and the obtained free-energies are those of a “ribbon” passing through the middle of the minor groove’s sampled volume. In this representation the DNA’s axis is at the center of the plot. Note that in this coordinate system there is no angular periodicity.

Mentions: Using all-atom umbrella sampling (US) MD simulations with the above-mentioned helical coordinate system, we calculated the PMF for a Na+ ion tracking the DNA’s minor groove to probe the roughness of the binding free energy landscape (Fig. 2). Notably, the free-energy landscape varies significantly along one helical turn, indicating a rough free energy surface, with large energy barriers and free energy minima. For example, in most cases, the sites of lowest free-energy are deeply buried in the minor groove (i.e. closer to the DNA’s axis). However, large free energy barriers were also identified (≳ 5 kcal/mol), possibly due to steric hindrance, as the ligands comes closer to the DNA’s axis or backbone. The large free-energy barrier in the first-quadrant (i.e. ϕ in the range from 0 to 90o) are due to the deformation of the DNA which causes a steric clash between the Na+ cation and the backbone between T5 and C6 of the 3’ to 5’ strand (S4 Fig.). On the other hand, at intermediate radii from the DNA’s axis (∼ 12 Å), the energy landscape becomes smoother (Fig. 3.A). Binding sites along the studied region are not necessarily well localized and can extend for several base pairs (Fig. 3.A). For the specific DNA sequence studied in this work, the computed energy landscape suggests that the Na+ ions localize to a 5 base-pair segment. Previous studies have determined that Na+ ions bind to AT rich regions for periods of 50 ns [3]. These binding sites are the main contributors to slowly exchanging Na+ ions between the DNA’s minor groove and the surrounding bulk solvent [33]. Our calculations are in agreement with these findings, but suggest that once buried into the minor groove, Na+ ions may easily slide along the helical path, moving slightly away from the helical axis during sliding, when needed.


DNA exit ramps are revealed in the binding landscapes obtained from simulations in helical coordinates.

Echeverria I, Papoian GA - PLoS Comput. Biol. (2015)

Binding free-energy landscape for Na+ in the minor groove: The PMF was computed for one complete turn (2π) along the minor groove in the helical coordinates system (see S1 Fig.).The PMF was projected to the 2D plane, such that the ξ-axis is perpendicular to the page (see Methods sections and S1 Fig.) and the obtained free-energies are those of a “ribbon” passing through the middle of the minor groove’s sampled volume. In this representation the DNA’s axis is at the center of the plot. Note that in this coordinate system there is no angular periodicity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4326129&req=5

pcbi.1003980.g002: Binding free-energy landscape for Na+ in the minor groove: The PMF was computed for one complete turn (2π) along the minor groove in the helical coordinates system (see S1 Fig.).The PMF was projected to the 2D plane, such that the ξ-axis is perpendicular to the page (see Methods sections and S1 Fig.) and the obtained free-energies are those of a “ribbon” passing through the middle of the minor groove’s sampled volume. In this representation the DNA’s axis is at the center of the plot. Note that in this coordinate system there is no angular periodicity.
Mentions: Using all-atom umbrella sampling (US) MD simulations with the above-mentioned helical coordinate system, we calculated the PMF for a Na+ ion tracking the DNA’s minor groove to probe the roughness of the binding free energy landscape (Fig. 2). Notably, the free-energy landscape varies significantly along one helical turn, indicating a rough free energy surface, with large energy barriers and free energy minima. For example, in most cases, the sites of lowest free-energy are deeply buried in the minor groove (i.e. closer to the DNA’s axis). However, large free energy barriers were also identified (≳ 5 kcal/mol), possibly due to steric hindrance, as the ligands comes closer to the DNA’s axis or backbone. The large free-energy barrier in the first-quadrant (i.e. ϕ in the range from 0 to 90o) are due to the deformation of the DNA which causes a steric clash between the Na+ cation and the backbone between T5 and C6 of the 3’ to 5’ strand (S4 Fig.). On the other hand, at intermediate radii from the DNA’s axis (∼ 12 Å), the energy landscape becomes smoother (Fig. 3.A). Binding sites along the studied region are not necessarily well localized and can extend for several base pairs (Fig. 3.A). For the specific DNA sequence studied in this work, the computed energy landscape suggests that the Na+ ions localize to a 5 base-pair segment. Previous studies have determined that Na+ ions bind to AT rich regions for periods of 50 ns [3]. These binding sites are the main contributors to slowly exchanging Na+ ions between the DNA’s minor groove and the surrounding bulk solvent [33]. Our calculations are in agreement with these findings, but suggest that once buried into the minor groove, Na+ ions may easily slide along the helical path, moving slightly away from the helical axis during sliding, when needed.

Bottom Line: The computed PMFs show that, even for small ligands, the free energy landscapes are complex.For example, we identified the presence of dissociation points or "exit ramps" that naturally would terminate sliding.We discuss how our findings have important implications for understanding how proteins and ligands associate and slide along DNA.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, United States of America; Institute for Physical Science and Technology, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
DNA molecules are highly charged semi-flexible polymers that are involved in a wide variety of dynamical processes such as transcription and replication. Characterizing the binding landscapes around DNA molecules is essential to understanding the energetics and kinetics of various biological processes. We present a curvilinear coordinate system that fully takes into account the helical symmetry of a DNA segment. The latter naturally allows to characterize the spatial organization and motions of ligands tracking the minor or major grooves, in a motion reminiscent of sliding. Using this approach, we performed umbrella sampling (US) molecular dynamics (MD) simulations to calculate the three-dimensional potentials of mean force (3D-PMFs) for a Na+ cation and for methyl guanidinium, an arginine analog. The computed PMFs show that, even for small ligands, the free energy landscapes are complex. In general, energy barriers of up to ~5 kcal/mol were measured for removing the ligands from the minor groove, and of ~1.5 kcal/mol for sliding along the minor groove. We shed light on the way the minor groove geometry, defined mainly by the DNA sequence, shapes the binding landscape around DNA, providing heterogeneous environments for recognition by various ligands. For example, we identified the presence of dissociation points or "exit ramps" that naturally would terminate sliding. We discuss how our findings have important implications for understanding how proteins and ligands associate and slide along DNA.

Show MeSH
Related in: MedlinePlus