A Transferable Deprotonated Tyrosine Residue for Amber and CHARMM Force Fields

The deprotonated form of tyrosine gates proton-coupled electron transfer (PCET) in ribonucleotide reductase and photosystem II, forms the anionic chromophore of fluorescent proteins, and acts as a general acid/base in enzymes, yet a validated, transferable tyrosinate residue for routine fixed-charge protein simulations in the major Amber and CHARMM force fields is lacking. Here, we construct a deprotonated tyrosine residue (TYM) by transferring quinoid phenolate valence parameters, QM-validated for the fluorescent protein chromophore, and phenoxide parameters to standard Amber14/19/99SB* and CHARMM36m force fields. We validate the deprotonated residue against ab initio molecular dynamics simulations of a tyrosine side chain analog in water and experimental protein tyrosine p K a values. The best-performing force fields attain an AUE of roughly 0.5 p K units across 17 residues and preserve the catalytic Tyr57–Tyr16 hydrogen bond in ketosteroid isomerase. Finally, as an application, we combine the parameters with a 2 n protonation microstate treatment of residue coupling to obtain a ground-state protonation landscape for the E. coli ribonucleotide reductase radical transfer pathway without introducing radical-specific parameters.