We had submitted six hand-engineered predictions in Stage 1a and for all of them we obtained equal or better RMSD compared to our HYBRID-based protocol. In particular, for the ligand BACE_5 and BACE_16, the hand-engineered poses have an RMSD < 2 Å , while the respective RMSD of HYBRIDbased poses are > 2 Å (Fig. ). This highlights that a lot of work is still needed in order to improve search algorithms to achieve better accuracy in binding mode predictions. We docked the ligands into the proteins and performed short 14 ns explicit solvent MD simulations. Finally, we scored the ligands using MM-GBSA calculations. At the end of the challenge, the organizers reported quality metrics (the Kendall's τ and the Spearman's ρ) to assess the correlation between the experimental and predicted affinity rankings for the 154 compounds. The overall correlation between our predicted binding affinity ranking and the experimental affinity ranking is rather poor for both the Kendall's τ and the Spearman's ρ. We have obtained a Kendall's τ of 0.17 and a respective Spearman ρ of 0.26 for our Stage 1a MM-GBSA based submission. Out of the 26 structure-based affinity ranking submissions in Stage 1a, our MM-GBSA based submission was classified as the 7 th (Fig. ), with the best submission in this category having a Kendall's coefficient and a Spearman's ρ of 0.38 and 0.54, respectively. There was also no improvement for the structure-based ranking between Stage 1a and Stage 2 indicating that our MM-GBSA protocol is not performing well in ranking the ligands from this affinity ranking set. For Stage 2, our MM-GBSA based submission was ranked 19 th among 48 submissions using the Kendall's τ correlation coefficients (Fig. ) and 18 th using the Spearman's ρ. The top submission scored a Kendall's τ of 0.39 and a Spearman's ρ of 0.54.