Typically, events such as conformational transitions in proteins or flexible ligands with large torsional barriers around rotatable bonds occurs abruptly, involving large changes of the relevant collective coordinate (e.g. a dihedral angle) in a subpicoseconds time scale. These rapid transitions, triggered by random collision or concerted fluctuations, are nonetheless rare, in the sense that few of them can be observed in a single molecule or flexible ligand on a time scale from nanoseconds to milliseconds. In many-molecules systems, rare events become frequent when we test their generic reduced probability of occurrence on any one of molecules. So, while observing a rare event on some molecule is common in a thermodynamic system, it is a matter of pure luck if one is monitoring the behavior of one single molecule during a typical MD simulation lasting few tens of ns. Recently, the advent of GPU and the porting of MD algorithms to GPU architectures has boosted the speed of popular MD codes by more than one order of magnitude. A typical solvated drug-receptor system in periodic boundary conditions (50K-100K atoms) can now be run for hundreds of ns per day on a high-end heterogeneous HPC platform. However, in many cases, this time span can be insufficient for obtaining a statistically converged simulations, since we are dealing with a single-molecule system and not with a thermodynamic ensemble. Unconverged runs on single complexes typically plague the final outcome of the prediction using FEP or TI-based alchemical approaches for binding free energy calculations. The sampling problem is patently exposed when results are found to critically depend on similar starting conditions so that in general replicates of costly alchemical free energy calculations must be often carried to deliver a reliable prediction with a credible confidence interval. Enhanced sampling techniques are often used to overcome these sampling-related issues. HREM is certainly one of the most effective advanced MD methods for simulating systems with rugged conformational landscapes. HREM is generally engineered to be collective coordinate ag-nostic, scaling the full potential energy of the system or a part of it as in the so-called solute tempering scheme. This is a significant advantage in drug-receptor systems where we do not generally know a priori which collective variables are involved in induced fit or regulating allosteric effects.