A solution to this problem is the use of enhanced sampling approaches to improve the sampling of the energy surface. As outlined in Ref. , such methods largely fall into four classes: (I) path sampling techniques that focus on improving the sampling of transitions between two pre-defined states of the system, (II) tempering or generalized ensemble approaches, that enhance sampling by modifying the system Hamiltonian to lower barrier heights, (III) decomposition techniques, and (IV) collective variable (CV) based biasing techniques . Here, our focus is on the second of these, and in particular on replica exchange molecular dynamics (MD), which is a CV-independent advanced generalized ensemble sampling technique . Many different flavors of this approach have been developed , however, at its core, REMD enhances the sampling of the system by running multiple replicas in parallel at different temperatures, and exchanging the temperature of non-interacting replicas at given intervals in order to overcome multiple-minima. As a CVindependent approach, REMD provides the benefit of not requiring prior knowledge of the system being studied (which would otherwise be a pre-requisite for the selection of an appropriate reaction coordinate) . However, the computational cost of this approach, in terms of the number of replicas, and the sampling time needed for convergence, increases with the size of the system .