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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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Radial distribution functions (gOW−cation) of water oxygens around the methyl-guanidinium cation.A) gOW−cation computed at different radii from the DNA’s axis. B) Average number of water oxygen atoms 〈N〉 in the first hydration of the methyl-guanidium cation at different radius from the DNA’s axis.
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pcbi.1003980.g007: Radial distribution functions (gOW−cation) of water oxygens around the methyl-guanidinium cation.A) gOW−cation computed at different radii from the DNA’s axis. B) Average number of water oxygen atoms 〈N〉 in the first hydration of the methyl-guanidium cation at different radius from the DNA’s axis.

Mentions: As the methyl-guanidinium ligand is removed from the minor groove, the head group shows partial dehydration, as shown by the radial distribution function gOW−cation (Fig. 7). This non-trivial hydration profile suggests that the largest dehydration occurs at an intermediate range of radii between 11 and 12 Å off the DNA’s axis (Fig. 7.B), which coincides with the position of the DNA’s phosphate groups. Consequently, the methyl-guanidinium ligands become partially dehydrated as they get into the minor groove, but once further buried into the minor groove, water molecules relocalize to the first hydration shell. Fig. 7.A also indicates partial dehydration of the second hydration shell for methyl-guanidinium cations buried in the minor groove. These hydration patterns reveal the presence of water mediated interactions [36, 37] between the methyl-guanidinium ligand and the DNA molecule. These observations suggest that the free-energy barriers of radial ligand movement not only depend on the electrostatic potential inside the minor groove but also on the sizes and the hydration levels of the ligand.


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

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

Radial distribution functions (gOW−cation) of water oxygens around the methyl-guanidinium cation.A) gOW−cation computed at different radii from the DNA’s axis. B) Average number of water oxygen atoms 〈N〉 in the first hydration of the methyl-guanidium cation at different radius from the DNA’s axis.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1003980.g007: Radial distribution functions (gOW−cation) of water oxygens around the methyl-guanidinium cation.A) gOW−cation computed at different radii from the DNA’s axis. B) Average number of water oxygen atoms 〈N〉 in the first hydration of the methyl-guanidium cation at different radius from the DNA’s axis.
Mentions: As the methyl-guanidinium ligand is removed from the minor groove, the head group shows partial dehydration, as shown by the radial distribution function gOW−cation (Fig. 7). This non-trivial hydration profile suggests that the largest dehydration occurs at an intermediate range of radii between 11 and 12 Å off the DNA’s axis (Fig. 7.B), which coincides with the position of the DNA’s phosphate groups. Consequently, the methyl-guanidinium ligands become partially dehydrated as they get into the minor groove, but once further buried into the minor groove, water molecules relocalize to the first hydration shell. Fig. 7.A also indicates partial dehydration of the second hydration shell for methyl-guanidinium cations buried in the minor groove. These hydration patterns reveal the presence of water mediated interactions [36, 37] between the methyl-guanidinium ligand and the DNA molecule. These observations suggest that the free-energy barriers of radial ligand movement not only depend on the electrostatic potential inside the minor groove but also on the sizes and the hydration levels of the ligand.

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