Rate-limiting transition. Rate-limiting transition. (A) Transition between states S3–S4 often occurs as pictured. Benzamidine rolls over trypsin’s surface by a set of successive transient interactions (transition states) TS1, TS2, and TS3 that canalizes the penetration of the inhibitor to its binding pocket. (B) Transition states are defined by the hydrogen-bond interactions formed between benzamidine and N89 main chain (TS1), with H57 main chain and S210 side chain (TS2), and finally with S214 main chain (TS3). Far from all binding trajectories following exactly this path; some trajectories bind passing only from TS2 and TS3, or directly to TS3, prior to burying into the binding pocket at the known bound conformation. As a side note, H57 belongs to the trypsin catalytic triad, responsible for the peptide bond cleavage activity of serine proteases. Ignasi Buch et al. PNAS 2011;108:25:10184-10189