In recent years, a lot of effort has been made to develop workflows that simplify and automate the process of free energy calculations , which includes steps to plan, set up and execute simulations, and to analyse the final results. There are a few automated pipelines developed for free energy calculations, including commercial ones like FEP+ and Molecular Operating Environment (MOE) , and non-commercial ones like Amber free energy workflow (FEW) , FESetup 11 , FEPrepare , CHARMM-GUI FEP calculator , to name just a few. The workflows have found promising applications in academia as well as industry. FEP+ , for example, is the free energy calculation suite from Schrödinger Inc. that has made a significant impact in the pharmaceutical industry. To obtain reliable and reproducible free energy estimation, we have developed two ensemble-based protocols in the last few years, named ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) . ESMACS is an end-point approach based on the molecular mechanics Poisson-Boltzmann surface area method (MMPBSA) , and TIES is an alchemical approach centred on thermodynamic integration (TI). We recently made a systematic uncertainty quantification (UQ) analysis of molecular simulations and binding free energy estimations, and showed that ensembles can be invoked to acquire robust statistical measures of uncertainty, which address both parametric and stochastic components of MD simulations . The names of our methods emphasise the central importance of the ensemble-based nature of the protocols employed . Ensemble approaches lead to increased reliability and reproducibility, with tighter control of standard errors revealing the distribution of results that can be obtained . ESMACS and TIES are performed using a binding affinity calculator (BAC) , a computational pipeline designed to automate the end-to-end execution of free energy calculations, and to handle ensemble calculations.