Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Oct 14;139(14):144903.
doi: 10.1063/1.4822042.

An experimentally-informed coarse-grained 3-Site-Per-Nucleotide model of DNA: structure, thermodynamics, and dynamics of hybridization

Daniel M Hinckley  1 , Gordon S Freeman, Jonathan K Whitmer, Juan J de Pablo
Affiliations

An experimentally-informed coarse-grained 3-Site-Per-Nucleotide model of DNA: structure, thermodynamics, and dynamics of hybridization

Daniel M Hinckley et al. J Chem Phys. .

Abstract

A new 3-Site-Per-Nucleotide coarse-grained model for DNA is presented. The model includes anisotropic potentials between bases involved in base stacking and base pair interactions that enable the description of relevant structural properties, including the major and minor grooves. In an improvement over available coarse-grained models, the correct persistence length is recovered for both ssDNA and dsDNA, allowing for simulation of non-canonical structures such as hairpins. DNA melting temperatures, measured for duplexes and hairpins by integrating over free energy surfaces generated using metadynamics simulations, are shown to be in quantitative agreement with experiment for a variety of sequences and conditions. Hybridization rate constants, calculated using forward-flux sampling, are also shown to be in good agreement with experiment. The coarse-grained model presented here is suitable for use in biological and engineering applications, including nucleosome positioning and DNA-templated engineering.

PubMed Disclaimer

Figures

Figure 1
Figure 1
(a) Comparison of all-atom and 3SPN.2 coarse-grained excluded volume representations of the Drew-Dickerson dodecamer (5′-CGCGAATTCGCG-3′). (b) Coarse-grained sites of 3SPN.2 superimposed on the all-atom representations. The coarse-grained sites are located at the centers of mass of the phosphate, sugar, or base. (c) Schematic representation of the angle-dependent non-bonded interactions acting between the base sites. The green arrows represent the base stacking potential UBS, the blue arrows represent the base pairing potential UBP, and the orange arrows represent the cross-stacking potential UCS. Figures were rendered using VMD.
Figure 2
Figure 2
Schematic representation of anisotropic base-base interactions. The inner yellow cone represents the angles wherein the full potential is applied. The volume of the outer green cone not included in the yellow cone represents the range of angles wherein the potential is modulated from its full value to zero. A parameter K controls the width of these cones, with a smaller value leading to a wider range of interactions. (a) Angle-dependence of the intra-strand base stacking interactions (K = 6). (b) Angle-dependence of one of the angles θ in the base pairing interactions (K = 12). (c) Angle-dependence of the cross-stacking interactions (K = 8). The shaded spheres represent the excluded volume of the DNA sites. Figures were rendered using VMD.
Figure 3
Figure 3
Definition of the angles used to modulate base-base interactions. (a) Intra-strand base stacking angle θBS, defined as the angle between Bi, the vector connecting a sugar and base site and rij, the vector connecting the base with its neighbor in the 3′ direction. (b) Base pairing angles, θ1, θ2, and ϕ1, are defined by the effective dihedral angle between the base pair; θ1 is the angle between vector Bi connecting the sugar and base on the sense strand and vector rij′ connecting the base on the sense strand with its complement, either on the anti-sense strand in the case of a duplex or the sense strand of a hairpin. Here θ2 is the angle between vector rij′ and vector Bj, connecting the sugar and base site of the complementary nucleotide. The angle ϕ1 is the dihedral angle defined by the vectors Bi, rij, and Bj. (c) cross-stacking angles, θ3 and θCS, are the angles between vectors Bi and Bj and vectors Bi and rij″, respectively. Here, rij″ is the vector connecting the base site on the sense strand to the base site adjacent to its W–C complement in the 5′ direction of the anti-sense strand. A similar vector is defined between the base site participating in a W–C base pair and the base site adjacent to its complement in the 3′ direction of the sense strand. The shaded spheres represent the excluded volume of the DNA sites. Figures were rendered using VMD.
Figure 4
Figure 4
Metadynamics, combined with an appropriate choice of order parameter, is used to quantify melting temperatures with 3SPN.2. The top panel shows a representative free energy surface for a DNA duplex (5′-TACTAACATTAACTA-3′) at the melting temperature calculated using the order parameters described in the text. (a)–(c) The positions in order parameter space of the configurations found on the right. The dashed green line indicates the approximate position of the saddle point used to differentiate between hybridized and dehybridized states. Note that beyond 90 Å the free energy surface has been extended analytically. The bottom panel shows a representative free energy surface for a DNA hairpin (5′-ATGCAATGCTACATATTCGCTTTTTGCGAATATGTAGCATTGCAT-3′) at its melting temperature using the same order parameters as in the case of the duplex. (d)–(f) The locations of the configurations shown on the right. Again, the dashed green line on the free energy surface is used to separate hybridized and dehybridized states.
Figure 5
Figure 5
Interfaces used in FFS to calculate the reaction probability. χ is the normalized COM separation, Γ is the fraction of total possible W–C base pairs formed, and λi is depicted by the diagonal lines.
Figure 6
Figure 6
Representative 144 bp configurations of ssDNA (top) and dsDNA (bottom) from separate 3SPN.2 simulations at T = 300 K and I = 150 mM.
Figure 7
Figure 7
Scaling of persistence length (lp) with ionic strength I for various DNA coarse-grained models with explicit charges. All results have been scaled such that the persistence length at I = 150 mM is 500 Å.
Figure 8
Figure 8
(Top) Agreement between experimental and simulated melting temperature for duplexes and hairpins. (Bottom) Melting curves obtained from simulation showing the effect of oligomer concentration on calculated melting temperatures. The 4–5 K change in the measured melting temperature is consistent with experiment. The experimental data presented are from an oligomer concentration of 2 μM. Sequence: 5′-TACTTCCAGTGCTCAGCGTA-3′; I = 69 mM.
Figure 9
Figure 9
Comparison of simulated hybridization rate constants to experimental rates constants from Ref. . Error bars represent the standard error in the mean.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Perez A., Luque F. J., and Orozco M., Acc. Chem. Res. 45, 196 (2012).10.1021/ar2001217 - DOI - PubMed
    1. Lyubartsev A. P. and Nordenskiöld L., J. Phys. Chem. B 101, 4335 (1997).10.1021/jp963982w - DOI
    1. Kornyshev A. A. and Leikin S., Proc. Natl. Acad. Sci. U.S.A. 95, 13579 (1998).10.1073/pnas.95.23.13579 - DOI - PMC - PubMed
    1. Jian H., Vologodskii A. V., and Schlick T., J. Comput. Phys. 136, 168 (1997).10.1006/jcph.1997.5765 - DOI
    1. Jendrejack R. M., de Pablo J. J., and Graham M. D., J. Chem. Phys. 116, 7752 (2002).10.1063/1.1466831 - DOI

Publication types

LinkOut - more resources