The 'electrostatic handle' mechanism of CypA proposes that catalytic activity is driven by the alignment of a large electric field (provided by the R55 residue in WT CypA) with the carbonyl dipole of the residue preceding the substrate proline in the transition state. Our results with both AMOEBA and additive force fields are consistent with a significant contribution of R55 to the overall electric field in both CypA ground states. However, the magnitude of this contribution (taken as the difference between mean fields in the WT and R55A simulations) appears to be smaller than that proposed by Camilloni and coworkers, with a maximum of -8.7 MV cm -1 for the cis-proline or -23.5 MV cm -1 for the trans-proline system across all AMOEBA simulations (Table ), rather than the ca. -30 MV cm -1 estimated previously. The comparisons of QM and MM electric fields performed here were not designed specifically to probe the CypA mechanism, and there may be multiple reasons for the observed discrepancies in field strengths.