With the exception of the TI cases with rapid changes of the gradient in the end states, both TI and FEP methods achieve comparable accuracy and precision for the systems studied in this work and as such neither TI or MBAR is highlighted as preferred. In the occasional TI case which provided problems with the end states, issues were treated easily by choosing appropriate soft-core parameters. What is clear is the benefit of using both TI and FEP results in tandem to check the results of the other. Whilst using many MD packages to check the reproducibility of results incurs significantly more cost and may not always be practical, the use of two or more free energy estimators incurs little additional cost and, as shown in this work, can aid in the identification and diagnosis of alchemical protocol, specific issues causing poor accuracy or precision in the results .