Regarding the batch strategies, the KB batch strategy appears to perform better than the naive top-k approach (Fig. and S16), although both batch strategies fall within the confidence interval. In contrast, the CL batch strategy, which seeks batches with greater sequence diversity, does not perform well in the context of MHC class I. These results suggest that simpler batch strategies might be equally effective as more complex ones in the context of peptide optimization. Extensive examples in the literature has shown that even small structural changes or single mutation can lead to large potency effects (i.e. activity cliff), and these structure-activity discontinuities are difficult to capture using 2D information only . Therefore, it can be argued that biasing the search towards higher peptide sequence diversity, as done with the CL batch strategy, is not required and may not be the most effective approach, and resulting in missed opportunities.