The discovery and design of novel drugs is immensely expensive, with one study putting the cost of each new therapeutic molecule that reaches the clinic at US$1.8 billion . A diversity of computational approaches, specifically binding free energy calculations which rely on physics-based molecular dynamics simulations (MD) have been developed and blind tests show that many have considerable predictive potential . In this context, recent developments in algorithms and hardware that have reduced the cost of these computational approaches have seen an increase in their appeal to the pharmaceutical industry . With commercial approaches that claim accuracy of below 1 kcal mol -1 now on the market it is becoming of increasing interest to understand the accuracy of and uncertainties inherent in different approaches . These concerns echo wider interest in the scientific community in the lack of reproducible results in the published literature .