Molecular dynamics (MD) simulations are commonly used to calculate the time evolution of various (bio)chemical systems, ranging in size from short-timescale simulations of atomic collisions in vacuo to μs-timescale simulations of large biomolecular systems. However, the complexity of the underlying energy landscapes and the long timescales of the processes involved remains a challenge : molecular dynamics simulations typically use step sizes on the order of the fastest motion of the system. This is generally limited by bond-stretching and bending, and is on the order of 10 -15 s, with specialized approaches such as hydrogen mass repartitioning allowing for timesteps of up to 4 fs . However, most biochemical processes of interest take place on the millisecond timescale and beyond , putting many of them out of the reach of conventional (unbiased) MD simulations. In addition, this means that the ergodicity principle might not be fulfilled for such systems, as a result of insufficient sampling due to too short simulation times .