The quantity ∆E int represents the interaction energy averaged over a molecular dynamics trajectory, and results for 1LI2 indicate that ∆E int converges in fewer than 100 snapshots. The correction ∆G • solvn be estimated using implicit solvation models that are compatible with large-scale electronic structure calculations. 106,119 Finally, ∆S vib can be computed from DFT (or perhaps semi-empirical) vibrational frequency calculations. These corrections are not included in the present work, however, as our focus is to establish fragment-based protocols to compute ∆E int . As such, we do not expect to recover ∆G • bind in these calculations. In selecting between DFT and semi-empirical methods, or between double-and triple-ζ DFT methods, it is worth considering what level of accuracy is required from the calculations at hand. Convergence of ensemble averages ∆E int using single-pose interaction energies ∆E int appears to be rapid, using classical molecular dynamics to sample structures, yet the result will not approximate ∆G • bind without a calculation of S vib . The latter requires vibrational frequency calculations, as SASAdependent corrections are insufficient to bridge the quantitative gap between ∆E int and ∆G • bind . As compared to the disparity between these two values, changes in ∆E int with respect to n-body order are small.