Ribonuclease A is the oldest model for studying enzymatic mechanisms, yet questions remain about proton transfer within the active site. Seminal work by Jackson et al. (1994) labeled Ribonuclease A with 4-fluorohistidine, concluding that active-site histidines act as general acids and bases. Calculations of 4-fluorohistidine indicate that the pi-tautomer is predominant in all simulated environments (by similar to 17 kJ/mol), strongly suggesting that fluoro-labeled ribonuclease A functions with His119 in pi-tautomer. The tautomeric form of His119 during proton transfer and tautomerism as a putative mechanistic step in wild-type RNase A remain open questions and should be considered in future mechanistic studies. (C) 2016 Elsevier B. V. All rights reserved.