The interplay between compound tail positioning and conformation of TbPTR1 substrate loop. As observed previously, the substrate loop that flanks subpocket C and interacts with the inhibitors' tails adopts slightly differing conformations in different TbPTR1 crystal structures . Notably, since the inhibitors' tails are flexible, the preferences for either subpocket C or D may be related to the conformation of the substrate loop. Indeed, in the complexes with compounds 2b and 2d, targeting subpocket C, we observe a slight rotation of the indole moiety of Trp221 by 25-37 • with respect to the conformation in the complexes with compound tails occupying subpocket D (Fig. ). Therefore, the conformational change of Trp221 appears to be associated with the presence of substituents in subpocket C of TbPTR1. Overall, the flexibility of Trp221 might play a role in the inhibitor binding process and may affect binding affinities of the compounds through the entropic contribution to binding free energy.