Using two different approaches to forming artificial metalloenzymes, a library of successful catalysts for the Cu-catalysed Friedel Crafts alkylation were obtained. Moderate activities and good enantiomeric ratios were observed with SCP_Q111BpyAla giving the highest e.r. of 14:86 in favour of the S enantiomer. In general, lower enantioselectivities were observed for the cysteine-modified catalysts and this is attributed to increased flexibility around the active site due to the additional S-CH2 linker. Changing from genetic incorporation of BpyAla at Q111 to bioconjugation of bipyridine through a cysteine, resulted in an unexpected change in the major isomer observed from S to R, albeit with a reduction in enantiomeric excess. This result is intriguing as a major challenge in enzyme catalysis is accessing the opposite product enantiomer. Crystallographic and computational studies confirm that changes in the structure of the active site led to the stabilisation of indole 3 on different sides of the bound enone 4, with the enantiomeric ratios observed correlating with the difference in the calculated transition state energies for the proR and proS SCP_Q111BpyAla and SCP_Q111CBpy Cu catalyst models. Based on these findings, future work should prioritize determining the most suitable modification method for the desired application of the ArM before proceeding with reaction screening and optimization, as subtle differences in protein structure can substantially change the stabilised transition state.