In the last few years, our team at UCL has developed two ensemble-based protocols for free energy calculations, termed "enhanced sampling of molecular dynamics with approximation of continuum solvent" (ESMACS) and "thermodynamic integration with enhanced sampling" (TIES) . ESMACS is based on the molecular mechanics Poisson-Boltzmann surface area method (MMPBSA) while TIES centres on thermodynamic integration (TI). Although the protocols are built around the standard MMPBSA and TI methodologies, the names and abbreviations of these protocols are used to emphasise the central importance of the ensemble based nature of the protocols employed . The term "ensemble" here refers to a set of individual (often called "replica") simulations conducted for the same physical system, starting from different initial conformations (and possibly also with varying model parameters ). Advances in high-end computing capabilities offer the opportunity to run all of the replicas concurrently, ensuring the results can be delivered rapidly, exactly as has been done in climate and weather forecasting for the past twenty years. Ensemble approaches lead to increased reliability and reproducibility, with tighter control of standard uncertainty for nonlinear systems which are chaotic in nature . ESMACS and TIES are performed using a binding affinity calculator (BAC) which is a computational pipeline to automate the processes of building, running and marshalling the molecular dynamics simulations, as well as collecting and analysing data.