  The computational study of conformational transitions in RNA and proteins
with atomistic molecular dynamics often requires suitable enhanced sampling
techniques. We here introduce a novel method where concurrent metadynamics are
integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is
built with different strength of the bias potential exploiting the tunability
of well-tempered metadynamics. Using this method, free-energy barriers of
individual collective variables are significantly reduced compared with simple
force-field scaling. The introduced methodology is flexible and allows adaptive
bias potentials to be self-consistently constructed for a large number of
simple collective variables, such as distances and dihedral angles. The method
is tested on alanine dipeptide and applied to the difficult problem of
conformational sampling in a tetranucleotide.
