In the long-timescale protocol, we perform ten or twelve replica simulations of 10 microseconds each. Each simulation is initiated from a common configuration in which the ligand is placed 20 Å from the surface of the protein with initial velocities drawn randomly from Maxwell-Boltzmann distribution. A simulation length of 10 microseconds is chosen on the basis that it is on the order of simulation times (microseconds to tens of microseconds) that have been utilised in multiple previous studies to derive information on the nature of ligand-protein interactions This protocol allows us to address two crucial aims within our study. First, we intend to identify whether a single 10 microsecond run can reliably reproduce the full range of binding sites and binding modes sampled by the aggregate of the "splitting" protocol (which has a length of 9 microseconds). And second, we aim to demonstrate the variability between the 10 microsecond members of the ensemble in order to examine whether a single "longtimescale" (ten microsecond) trajectory is capable of generating reproducible and therefore reliable results. Indeed, as we show, each 10-microsecond run exhibits different statistics due to the chaotic nature of MD trajectories. A few recent papers from the D. E. Shaw group implicitly recognise such variability in MD simulations at the microsecond timescale. However, this has not been studied systematically hitherto, nor has the importance of ensembles of simulations at long-timescale been discussed in the literature as we do in this study. were executed, amongst other papers which run on similar timescales. The purpose of the splitting method is to explore and identify as many binding sites as are feasible to which the ligand of interest may bind on the protein, whilst reducing the amount of wall time required to do so.