Comparing the TI and FEP estimators, two potential sources of error were investigated in detail. In the case of TI, errors can accumulate in the numerical integration if the potential has large curvature with respect to the alchemical parameters. This resulted in significant differences in the ∆∆G values estimated with TI and FEP. We saw this error manifest in NAMD calculations when examining the thrombin target. For the affected cases, rapid changes of the gradient in the initial and final alchemical states of the calculation were related to the soft-core parameters. Both OpenMM, which used a softer soft-core potential, and NAMD, when rerun with a softer soft-core potential, exhibited no significant difference in the TI and FEP results. The second source of differences in TI and FEP results investigated here stemmed from the overlap in energy distributions of neighbouring alchemical states.