At the simplest level, our simulations show, in agreement with structural data, that the enzymes TrpF, PriA and HisA have increasingly large (in terms of active site volume) and "breathable" active sites (Table ), allowing for the accommodation of substrate ProFAR by HisA and PriA unlike PRA-specific TrpF, the active site of which is clearly too small to accommodate the larger substrate. More importantly, HisA and PriA both possess "gripper residues" interacting with the non-reactive phosphodianion group of ProFAR (R83 and S103 in HisA, R85 and T105 in PriA, Figure ) that are very similar to analogous interactions in other enzymes activated by ligand-gated conformational changes, such as TPI. Of note, however, is that the HisA/PriA "gripper" residues are contributed from the less mobile loops 3 and 4, unlike the primary gripper loop, loop 6 in TPI, which undergoes a substantial conformational change upon ligand binding. Other TIM-barrel proteins such as OMPDC possess analogous gripper loops to TPI loop 6, showing evidence for convergent evolution on these different (βα)8-barrel scaffolds.