Molecular dynamics
simulations are often used to provide feedback
in the design workflow of DNA nanostructures. However, even with coarse-grained
models, the 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 nonergodic, including bistable Holliday junctions and
part of a bistable DNA origami structure. Taking a DNA 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
exemplify the efficient computation of 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.