MrDNA: a multi-resolution model for predicting the structure and dynamics of DNA systems

Christopher Maffeo, and Aleksei Aksimentiev
Nucleic Acids Research (2020)
DOI:10.1093/nar/gkaa200  BibTex

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Designing a complex DNA nanostructure can be a time-consuming process that can involve rounds of experimental characterization that prompt modification to the design. Complementing this approach, we present a multi-resolution simulation framework called mrdna that can quickly characterize a DNA nanostructure, producing an atomistic model in as little as 10 minutes. We demonstrate fidelity of our mrdna framework through direct comparison of the simulation results with the results of cryo-electron microscopy (cryo-EM) reconstruction of multiple 3D DNA origami objects. We also show that our approach can characterize an ensemble of conformations adopted by dynamic DNA nanostructures, the equilibrium structure and dynamics of DNA objects constructed using off-lattice self-assembly principles, i.e. wireframe DNA objects, and the properties of DNA objects under a variety of environmental conditions, such as applied electric field. Implemented as an open source Python package, our framework can be extended by the community and integrated with DNA design and molecular graphics tools. The framework also powers our DNA origami structure prediction service. A tutorial covers both basic (command line) and advanced (scripting) usage of the mrdna framework.

Abstract

Although the field of structural DNA nanotechnology has been advancing with an astonishing pace, de novo design of complex 3D nanostructures and functional devices remains a laborious and time-consuming process. One reason for that is the need for multiple cycles of experimental characterization to elucidate the effect of design choices on the actual shape and function of the self-assembled objects. Here, we demonstrate a multi-resolution simulation framework, mrdna, that, in 30 min or less, can produce an atomistic-resolution structure of a self-assembled DNA nanosystem. We demonstrate fidelity of our mrdna framework through direct comparison of the simulation results with the results of cryo-electron microscopy (cryo-EM) reconstruction of multiple 3D DNA origami objects. Furthermore, we show that our approach can characterize an ensemble of conformations adopted by dynamic DNA nanostructures, the equilibrium structure and dynamics of DNA objects constructed using off-lattice self-assembly principles, i.e. wireframe DNA objects, and to study the properties of DNA objects under a variety of environmental conditions, such as applied electric field. Implemented as an open source Python package, our framework can be extended by the community and integrated with DNA design and molecular graphics tools.

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A typical mrdna simulation used to computationally resolve the structure of the 3D DNA origami "pointer" designed by the Dietz group. The coarse-grained simulation occurs in three stages: (1) a 5-bp/bead model is mapped into (2) a 2-bead/bp model that explicitly represents the orientation of each basepair but allows the linking number of the DNA to change, followed by (3) a 2-bead/bp model with a fixed linking number. The final configuration is mapped into an all-atom model suitable for subsequent refinement using the ENRG-MD method.

Comparison of the structural models obtained through an 5-bp/bead mrdna simulation and cryo-EM reconstruction (EMD-2210) of the pointer structure. The simulated and experimental structures are depicted as isosurfaces of the CG bead (blue, 1 bp/Å3 isovalue) and electron (white, 0.08 isovalue) densities, respectively. The simulated structure was obtained by calculating the average coordinates from 16 independent trajectories.

Simulation of the "slider" origami nanostructure designed by the Castro group performed with a resolution 5 bp/bead and lasting 500 μs. The slider consists of a large base affixed to a six-helix bundle shaft (blue) that threads through a movable bearing (teal), which is tethered on opposite ends to the base and to the tip of the shaft by a total of twelve flexible linkers. A distribution of the distance between the bearing and the base extracted from the simulation was in overall good agreement with an equivalent distribution extracted from experimentally-produced TEM images of slider nanostructures.

The mrdna framework is powered by our GPU-accelerated biomolecular simulation engine, ARBD, which supports the application of external potentials that are defined on a grid. Here, this feature is used to demonstrate the electrostatic-driven nanopipette capture of a wireframe DNA nanostructure designed by the Högberg group using vHelix.