Throughout the discussion below, we consistently adhered to the so-called 'physics' convention for electric fields, i.e., a positive electric field is obtained when the direction vector runs from positive to negative charge, and vice versa (Figure ). Note that within this convention, a positive field stabilizes a molecular system with a negative dipole moment (µ), and vice versa (Figure ). To validate the quality of our computed OLEFs, we also set up an alternative workflow where electrostatic environments were determined from the permanent multipoles and induced dipoles extracted from (polarizable) AMOEBA force field calculations, performed through OpenMM (see Section S1 of the Supporting Information for the equations used to quantify the electrostatic contributions of each outputted component). For the test cases considered (see Section S2 and S3 of the Supporting Information), we observe that despite some local distortions in the electrostatic environments -particularly on the evaluation sites close to the atoms of the protein matrix -the overall OLEF patterns are fully retained. The fact that both fixed-charge and polarizable force fields reproduce the trends described below, provides confidence that our presented findings are robust.