From simulations of WT CypA, Camilloni et al. calculated the mean electric field component aligned perpendicular to the plane of the proline ring (chosen to be roughly normal to the peptide bond in either of the cis/trans ground states) to be stabilizing, but relatively small at -40 to -50 MV cm -1 . Solvatochromism experiments suggest this magnitude lies between the electric field strengths exerted on probe molecules by polar, hydrogen-bonding environments such as alcohols or water, and those exerted by apolar solvents such as hexane. The CypA active site is therefore likely to be representative of typical intramolecular field strengths encountered in protein environments with both polar and non-polar moieties. Potential energy surfaces calculated for a model proline dipeptide by Camilloni et al. also suggested that a field of -50 MV cm -1 aligned with the cis/trans transition state would lower the isomerization activation energy by approximately 30 kJ mol -1 , qualitatively consistent with experimentally observed reaction speed-ups over the uncatalyzed reaction. Nevertheless, the electrostatic handle hypothesis was proposed using CypA field strengths determined with ONIOM DFT calculations, the relatively high computational cost of which precludes the use of this approach to study electric fields in proteins more generally. The hypothesis does suggest, however, that CypA provides a well-suited test case to evaluate the ability of the AMOEBA force field to recreate electric fields in protein active sites, which would provide a much faster route to evaluating ground-state electrostatics, energetics and dynamics.