Thrust 3: An experimentally-informed coarse-grained 3-site-per-nucleotide model of DNA: Structure, thermodynamics, and dynamics of hybridization (2014)

Daniel M. Hinckley, Gordon S. Freeman, Jonathan K. Whitmer and Juan J. de Pablo

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.

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 U BS , the blue arrows represent the base pairing potential U BP , and the orange arrows represent the cross-stacking potential U CS . Figures were rendered using V