Biological pathways are subject to subtle manipulations that achieve a wide range of functional variation in differing physiological niches. In many instances, changes in the structure of an enzyme on ligand binding germinate electrostatic perturbations that form the basis of its changed catalytic or transcriptional efficiency. Computational methods that seek to gain insights into the electrostatic changes in enzymes require expertise to setup and computing prowess. In the current work, we present a fast, easy and reliable methodology to compute electrostatic perturbations induced by ligand binding (MEPP). The theoretical foundation of MEPP is the conserved electrostatic potential difference (EPD) in cognate pairs of active site residues in proteins with the same functionality. Previously, this invariance has been used to unravel promiscuous serine protease and metallo-β-lactamase scaffolds in alkaline phosphatases. Given that a similarity in EPD is significant, we expect differences in the EPD to be significant too. MEPP identifies residues or domains that undergo significant electrostatic perturbations, and also enumerates residue pairs that undergo significant polarity change. The gain in a certain polarity of a residue with respect to neighboring residues, or the reversal of polarity between two residues might indicate a change in the preferred ligand. The methodology of MEPP has been demonstrated on several enzymes that employ varying mechanisms to perform their roles. For example, we have attributed the change in polarity in residue pairs to be responsible for the loss of metal ion binding in fructose 1,6-bisphosphatases, and corroborated the pre-organized state of the active site of the enzyme with respect to functionally relevant changes in electric fields in ketosteroid isomerases.