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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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Related in: MedlinePlus

The minor groove environment.A) Electrostatic potential inside the minor groove. The potential has been rescaled such that the minima in the studied region was set to 0 to facilitate the comparison with the computed PMF. B) The minor groove width was computed using the software Curves [51]. Grey shadows correspond to one standard deviation. For examples of different structures see S5 Fig..
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pcbi.1003980.g006: The minor groove environment.A) Electrostatic potential inside the minor groove. The potential has been rescaled such that the minima in the studied region was set to 0 to facilitate the comparison with the computed PMF. B) The minor groove width was computed using the software Curves [51]. Grey shadows correspond to one standard deviation. For examples of different structures see S5 Fig..

Mentions: Fig. 6.A shows the 2D projections of the electrostatic potential inside the minor groove along one DNA turn, analogous to the 2D projections of the 3D-PMF (Fig. 5.B). The Pearson’s correlation between the free-energy (Fig. 4.A) and potential energy (Fig. 6.A) is r≃0.91. This result supports the view that the enhanced electrostatic potential in the minor groove is a key determinant of the free-energy landscape. Furthermore, the computed DNA’s minor groove width (Fig. 6.B) shows that, along the studied turn, there are two narrower segments. Qualitatively, the location and depth of the free-energy minima (Fig. 5.B) correlate with the narrow regions of the minor groove (correlation coefficient r≃0.82, Fig. 6.B) and electrostatic potentials (Fig. 6.A), in agreement with Honig and co-workers [28, 35]. However, at some different radii, the free energy profiles (Fig. 5.A) do not correlate well with the widths of the minor groove. This might have important implications for proteins binding and sliding along DNA, as further elaborated below. In addition, in the studied spatial region around the DNA segment, the ranges of the free energy differences and the electrostatic potentials differ from each other, being 5.3 kcal/mol and 3.5 kcal/mol, respectively. This range difference is most likely associated with the inaccurate treatment of complex hydration effects in the minor groove when using continuum electrostatic approaches, as well as the importance of non-electrostatic interactions. Given the high charge density of the DNA backbone, it is expected that the binding free-energy (Fig. 5) and electrostatic potential (Fig. 6) landscapes are not completely smooth at large distances (≳ 12 Å).


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

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

The minor groove environment.A) Electrostatic potential inside the minor groove. The potential has been rescaled such that the minima in the studied region was set to 0 to facilitate the comparison with the computed PMF. B) The minor groove width was computed using the software Curves [51]. Grey shadows correspond to one standard deviation. For examples of different structures see S5 Fig..
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1003980.g006: The minor groove environment.A) Electrostatic potential inside the minor groove. The potential has been rescaled such that the minima in the studied region was set to 0 to facilitate the comparison with the computed PMF. B) The minor groove width was computed using the software Curves [51]. Grey shadows correspond to one standard deviation. For examples of different structures see S5 Fig..
Mentions: Fig. 6.A shows the 2D projections of the electrostatic potential inside the minor groove along one DNA turn, analogous to the 2D projections of the 3D-PMF (Fig. 5.B). The Pearson’s correlation between the free-energy (Fig. 4.A) and potential energy (Fig. 6.A) is r≃0.91. This result supports the view that the enhanced electrostatic potential in the minor groove is a key determinant of the free-energy landscape. Furthermore, the computed DNA’s minor groove width (Fig. 6.B) shows that, along the studied turn, there are two narrower segments. Qualitatively, the location and depth of the free-energy minima (Fig. 5.B) correlate with the narrow regions of the minor groove (correlation coefficient r≃0.82, Fig. 6.B) and electrostatic potentials (Fig. 6.A), in agreement with Honig and co-workers [28, 35]. However, at some different radii, the free energy profiles (Fig. 5.A) do not correlate well with the widths of the minor groove. This might have important implications for proteins binding and sliding along DNA, as further elaborated below. In addition, in the studied spatial region around the DNA segment, the ranges of the free energy differences and the electrostatic potentials differ from each other, being 5.3 kcal/mol and 3.5 kcal/mol, respectively. This range difference is most likely associated with the inaccurate treatment of complex hydration effects in the minor groove when using continuum electrostatic approaches, as well as the importance of non-electrostatic interactions. Given the high charge density of the DNA backbone, it is expected that the binding free-energy (Fig. 5) and electrostatic potential (Fig. 6) landscapes are not completely smooth at large distances (≳ 12 Å).

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