Modeling Secondary Structural Elements in Programmed DNA Assemblies

Abstract

Programmed self-assembly of single-stranded DNA offers a versatile approach to synthesizing complex macromolecular architectures with nanometer-scale precision. Structure-based mechanical modeling of these 3D assemblies plays an important role in their design due to the numerous challenges associated with their high-resolution structural characterization. Here, we use modeling to examine the impact of secondary structural elements including hairpin loops, gaps, bulges, internal loops, and multi-way junctions on overall 3D structure. Our approach focuses on the 3D structure prediction of diverse DNA nanoparticles on the 10 to 100 nanometer-scale including Platonic solids, bipyramids, Archimedean solids, and Catalan solids, which are structurally aligned with 3D cryo-EM maps for structural validation. We explore the relative roles of the ground-state geometry and mechanical properties of secondary structure elements, as well as ground-state interhelical distance and angle, on 3D nanoparticle structure, and elucidate general rules for their optimal design. Bayesian cryo-EM data analysis enables unbiased estimation of model parameter values and their uncertainties.