  Molecular dynamics simulations are often used to provide feedback in the
design workflow of DNA nanostructures. However, even with coarse-grained
models, convergence of distributions from unbiased simulation is slow, limiting
applications to equilibrium structural properties. Given the increasing
interest in dynamic, reconfigurable, and deformable devices, methods that
enable efficient quantification of large ranges of motion, conformational
transitions, and mechanical deformation are critically needed. Metadynamics is
an automated biasing technique that enables the rapid acquisition of molecular
conformational distributions by flattening free energy landscapes. Here we
leveraged this approach to sample the free energy landscapes of DNA
nanostructures whose unbiased dynamics are non-ergodic, including bistable
Holliday junctions and part of a bistable origami. Taking an origami compliant
joint as a case study, we further demonstrate that metadynamics can predict the
mechanical response of a full DNA origami device to an applied force, showing
good agreement with experiments. Our results establish an efficient framework
to study free energy landscapes and force response in DNA nanodevices, which
could be applied for rapid feedback in iterative design workflows and generally
facilitate the integration of simulation and experiments. Metadynamics will be
particularly useful to guide the design of dynamic devices for nanorobotics,
biosensing, or nanomanufacturing applications.
