We use ensembles of replica simulations (which here differ only in their initial particle velocities, drawn randomly from a Maxwell-Boltzmann distribution) in order to converge the statistics of the observable of interest. Whilst previous studies by our group have investigated the necessity of ensembles for accurate and precise ligand binding free energy calculations, here we aim to demonstrate that ensembles of MD simulations are equally essential for the accurate determination of ligand binding sites and ligand-protein interaction mechanisms. To do this, we conduct a thorough comparative analysis of two alternative ensemble protocols: