HIV-1 protease (HIV-P) is critical to the life cycle of HIV, facilitating the processing of precursor peptides to final, mature proteins . Although the specific mechanism is debated between concerted, oxyanion, and gem-diol mechanisms (Extended Data Fig. ) , we examine 𝐸𝐸 "⃗ (𝑟𝑟) that the protein scaffold exerts on the peptide bond through PyCPET. A study by Krzemińska and coworkers , on electrostatic preorganization in HIV proteases, emphasized two 𝐸𝐸 "⃗ (𝑟𝑟) components, one pointing toward the reactive aspartate residues and one along the direction of the peptide bond (Figure ). Another study demonstrated the importance of electron flow toward the C-N bond for two possible mechanisms, and the role of charged amino acids in reducing the barrier for both mechanisms .