Computing Nonequilibrium Conformational Dynamics of Structured Nucleic Acid Assemblies

Abstract

Synthetic nucleic acids can be programmed to form precise three-dimensional structures on the nanometer-scale. These thermodynamically stable complexes can serve as structural scaffolds to spatially organize functional molecules including multiple enzymes, chromophores, and force-sensing elements with internal dynamics that include substrate reaction-diffusion, excitonic energy transfer, and force-displacement response that often depend critically on both the local and global conformational dynamics of the nucleic acid assembly. However, high molecular weight assemblies exhibit long time-scale and large length-scale motions that cannot easily be sampled using all-atom computational procedures such as molecular dynamics. As an alternative, here we present a computational framework to compute the overdamped conformational dynamics of structured nucleic acid assemblies and apply it to a DNA-based tweezer, a nine-layer DNA origami ring, and a pointer-shaped DNA origami object, which consist of 204, 3,600, and over 7,000 basepairs, respectively. The framework employs a mechanical finite element model for the DNA nanostructure combined with an implicit solvent model to either simulate the Brownian dynamics of the assembly or alternatively compute its Brownian modes. Computational results are compared with an all-atom molecular dynamics simulation of the DNA-based tweezer. Several hundred microseconds of Brownian dynamics are simulated for the nine-layer ring origami object to reveal its long time-scale conformational dynamics, and the first ten Brownian modes of the pointer-shaped structure are predicted.

Structure and conformational dynamics of scaffolded DNA origami nanoparticles

“…The FE model of a single-stranded crossover is identical to that of a double-stranded crossover except that the rotational stiffness defined by pivoting about the reference axis z is reduced (Figure 1B) (72). In contrast, rotation about the x -axis or the y -axis results in steric overlap between the duplexes in the single crossover (Figure 1B).…”

“…Double and single-crossovers are treated explicitly by constraining the relative motions of joined duplexes, and bulges and open nicks are similarly modeled empirically using spring-like elements. A nonlinear FE solver is then used to compute the ground-state equilibrium structure (5,29,30) and mechanical properties of stable DNA assemblies, the latter comprising thermal fluctuations (29,30,72) and force-deformation responses (20), with significantly reduced computational cost compared with all-atom and nucleotide-level models. Previously, we introduced the FE framework CanDo (5,29) to compute equilibrium structures of a class of DNA assemblies in which DNA duplexes are placed on a honeycomb (16) or square (18) lattice.…”

Computational investigation of the impact of core sequence on immobile DNA four-way junction structure and dynamics

“…All simulations were performed using the program NAMD2 ( 76 ) with the CHARMM27 force field ( 77 , 78 ) and Allnér Mg 2 + ( 79 ) parameters. This procedure as follows has been successfully utilized in several previous studies of DNA origami nanostructures ( 80 , 81 ). An integration time step of 2 fs and periodic boundary conditions were applied in an orthogonal simulation cell.…”

Automated Quantification of the Impact of Defects on the Mechanical Behavior of Deoxyribonucleic Acid Origami Nanoplates

“…The increasing interest in DNA-based materials and devices has led to efforts to understand the mechanical properties of various DNA assemblies [18]. Mechanical modeling studies have largely focused on predicting the assembled structure geometry and flexibility [19], while a few experimental studies have used force spectroscopy [20,21] and imaging of thermal fluctuations [22] to quantify the mechanical properties of DNA nanostructures. These prior studies have led to a basic understanding of the mechanical stiffness, in particular bending stiffness, of various DNA assemblies and the ability to predict folded shapes including cases where local stresses lead to curvature [23,24].…”