Multi-Scale Structure and Conformational Dynamics of Scaffolded DNA Origami Nanoparticles

Synthetic DNA can be programmed into self-assembled 3D nanoparticles using a DX design motif and the principle of scaffolded DNA origami. A top-down design procedure (DAEDALUS) (Veneziano, Ratanalert, et al., Science, 2016) facilitates the design of arbitrary DNA nanoparticle geometries on the 5 to 100 nanometer scale, which we investigate in detail here using multi-scale structural modeling. While coarse-grained modeling is useful for generating equilibrium structures of DNA nanoparticles (Pan et al., Nat. Comm., 2014), only all-atom models reveal fine structural details and mechanical properties that contribute to overall structure and conformational dynamics. Here, we first use all-atom molecular dynamics (MD) to simulate two 0.5 - 1.0 MDa DNA polyhedral nanoparticles: a tetrahedron with 63 base pair (bp) edge lengths, and an octahedron with 52 bp edge lengths. Using 150 ns trajectories, we are able to elucidate subtle structural features seen in experimental cryo-EM maps, including right-handed twisting of the vertices in the octahedron and outward bowing of the edges in the tetrahedron. Next, these results are compared with all-atom MD simulations of unconstrained vertex building blocks including the tetrahedron (3-arm vertex) and octahedron (4-arm vertex). In these simulations, a notable feature is the significant out-of-plane bending angle away from the minor groove at the vertex due to the chirality of dsDNA. Finally, equilibrium solution structures of 45 DX-based DNA origami nanoparticles are predicted by implementing an updated bulge stiffness parameter for our coarse-grained FE model CanDo (Kim et al., Nucleic Acids Res., 2012). These multi-scale structural results show the interplay between coarse-grained and all-atom models in the ab initio prediction and elucidation of complex features of DNA nanoparticles seen in experimental cryo-EM maps.