HIV-1 protease (HIVPR) is an important drug target for combating AIDS. This enzyme is an aspartyl protease that is functionally active in its dimeric form. Nuclear magnetic resonance reports have convincingly shown that a pseudosymmetry exists at the HIVPR active site, where only one of the two aspartates remains protonated over the pH range of 2.5-7.0. To date, all HIVPR-targeted drug design strategies focused on maximizing the size-shape complementarity and van der Waals interactions of the small molecule drugs with the deprotonated, symmetric active site envelope of crystallized HIVPR. However, these strategies were ineffective with the emergence of drug resistant protease variants, primarily due to the steric clashes at the active site. In this study, we traced a specificity in the substrate binding motif that emerges primarily from the asymmetrical electrostatic potential present in the protease active site due to the uneven protonation. Our detailed results from atomistic molecular dynamics simulations show that while such a specific mode of substrate binding involves significant electrostatic interactions, none of the existing drugs or inhibitors could utilize this electrostatic hot spot. As the electrostatic is long-range interaction, it can provide sufficient binding strength without the necessity of increasing the bulkiness of the inhibitors. We propose that introducing the electrostatic component along with optimal fitting at the binding pocket could pave the way for promising designs that might be more effective against both wild type and HIVPR resistant variants.