From Fig. , we can also see that the formation of the tyrosyl radical ( ) is generally preferable to the formation of the histidyl radical (3). We thus consider it more likely that 2 and 3 are formed in competing reactions: the overall barrier for forming 2 via 3 is 199 kJ/mol for LsAA9, using [CuO] + (1) as a reference (see Fig. ). The barrier is lower for TaAA9, but with 149 kJ/mol, it must still be considered too high to be feasible. The high overall barrier may be a result starting from the Cu(II)-oxyl (1) species; we cannot exclude that another oxidative intermediate such as [Cu-OH] 2+ or a free OH radical is responsible for initiating the oxidative damage, and we are currently investigating such alternatives. However, if we consider the barrier for conversion 3→2 alone (in Fig. ), we still find that for LsAA9 the barrier is rather high (155 kJ/mol for B3LYP). It is interesting to compare this barrier (and reaction energy) to the 49 kJ/mol (and -287 kJ/mol) calculated for the recombination reaction of LsAA9 in ref. 35: this reaction is part of the oxidative damage pathway, where the formation of 3 is followed by recombination of the OH group from [Cu-OH] + in 3 to the histidyl radical, forming a 2-hydroxy-histidine. This reaction is evidently much more favorable than forming 3 -this is not changed if we look at the corresponding numbers for the overall reaction with the Cu(II)-oxyl (1), which were calculated to be 101 and -234 kJ/mol, respectively. Clearly, this is still more favorable than the 199 kJ/mol and -44 kJ/mol in Fig. . In conclusion, the formation of 3 is more likely to lead to oxidative damage than for 3 to be part of the protective hole-hopping mechanism, and this result is independent of choosing 1 as a reference.