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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Methyl-guanidinium sliding along the minor groove.A) 1D-PMFs of one turn along the helical path at different radii from the DNA’s axis. Grey shadow correspond to one standard deviation (see Methods section). B) Minimum free energy path obtained by assuming that, at every angular position, the ligand will localize the radii of minimum free energy. The PMF has been color coded to show the radius using the same color scheme as A).
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pcbi.1003980.g005: Methyl-guanidinium sliding along the minor groove.A) 1D-PMFs of one turn along the helical path at different radii from the DNA’s axis. Grey shadow correspond to one standard deviation (see Methods section). B) Minimum free energy path obtained by assuming that, at every angular position, the ligand will localize the radii of minimum free energy. The PMF has been color coded to show the radius using the same color scheme as A).

Mentions: We computed the 3D-PMF for the arginine analog, methyl guanidinium, to illustrate the positional free-energy of this ligand in the minor groove. At first sight, the 2D projection of the 3D-PMF (top view, Fig. 4.A) shows that the surface of the minor groove represents an intricate landscape with various local free-energy minima, with free-energy barriers of up to 5 kcal/mol. The 1D-PMFs computed at different angular locations (Fig. 4.B) show that the free-energy barriers to removing the ligand from the minor groove can vary significantly, ranging from 1.5 to 5 kcal/mol. These free-energy differences can be interpreted as the unbinding energies at different locations. On the other hand, the free-energy profiles of the ligand sliding along the helical path (Fig. 5.A) show energy barriers ranging from 0.5 to 1.5 kcal/mol. Additionally, the minimum free energy path along the studied turn (Fig. 5.B) indicates that a small free ligand, such as methyl guanidinium, would localize to a free energy minimum having a depth of 1.5 kcal/mol. Notably, the free-energy profiles vary significantly at different radii, indicating that, at an intermediate radius (i.e. ∼ 9.3 Å) the free-energy profile for sliding has the smallest barriers (≲ 0.8 kcal/mol). Consequently, in general, the energy barriers are smaller in the angular direction than in the radial direction, making sliding the preferred mechanism for moving methyl guanidinium along the DNA chain.


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

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

Methyl-guanidinium sliding along the minor groove.A) 1D-PMFs of one turn along the helical path at different radii from the DNA’s axis. Grey shadow correspond to one standard deviation (see Methods section). B) Minimum free energy path obtained by assuming that, at every angular position, the ligand will localize the radii of minimum free energy. The PMF has been color coded to show the radius using the same color scheme as A).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1003980.g005: Methyl-guanidinium sliding along the minor groove.A) 1D-PMFs of one turn along the helical path at different radii from the DNA’s axis. Grey shadow correspond to one standard deviation (see Methods section). B) Minimum free energy path obtained by assuming that, at every angular position, the ligand will localize the radii of minimum free energy. The PMF has been color coded to show the radius using the same color scheme as A).
Mentions: We computed the 3D-PMF for the arginine analog, methyl guanidinium, to illustrate the positional free-energy of this ligand in the minor groove. At first sight, the 2D projection of the 3D-PMF (top view, Fig. 4.A) shows that the surface of the minor groove represents an intricate landscape with various local free-energy minima, with free-energy barriers of up to 5 kcal/mol. The 1D-PMFs computed at different angular locations (Fig. 4.B) show that the free-energy barriers to removing the ligand from the minor groove can vary significantly, ranging from 1.5 to 5 kcal/mol. These free-energy differences can be interpreted as the unbinding energies at different locations. On the other hand, the free-energy profiles of the ligand sliding along the helical path (Fig. 5.A) show energy barriers ranging from 0.5 to 1.5 kcal/mol. Additionally, the minimum free energy path along the studied turn (Fig. 5.B) indicates that a small free ligand, such as methyl guanidinium, would localize to a free energy minimum having a depth of 1.5 kcal/mol. Notably, the free-energy profiles vary significantly at different radii, indicating that, at an intermediate radius (i.e. ∼ 9.3 Å) the free-energy profile for sliding has the smallest barriers (≲ 0.8 kcal/mol). Consequently, in general, the energy barriers are smaller in the angular direction than in the radial direction, making sliding the preferred mechanism for moving methyl guanidinium along the DNA chain.

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