We have performed ab initio calculation on the active site of HIV-1 protease. The FEP method was used to determine the binding free energy of four different of protonated states of HIV-1 protease with inhibitor. The structure of the active site and hole structure was taken from the X-ray crystallographic coordinates of the C2 symmetric inhibitor A74704 protease bound. The active site was modeled with the fragment molecules of binding pocket, acetic acid/acetate anion (Asp25, Asp 125), formamide (amide bond of Thr26/Gly27, Gly127), and methanol as inhibitor fragment. All possibly protonated states of the active site were considered, which were diprotonated state (0, 0), monoprotonated (-1, 0),(0, -1) and diunprotonated state (-1, -1). Once the binding energy ΔEbind, of each model was calculated, more probabilistic protonated states can be proposed from binding energy. From ab-initio results, the FEP simulations were performed for the three following mutations: I) Asp25 ⋯ Asp125 → AspH25 ⋯ Asp125, ii) Asp25 ⋯ Asp125 → Asp25 ⋯ AspH125, iii) AspH25 ⋯ Asp125 → AspH25 ⋯ AspH125. The free energy difference between the four states gives the information of the more realistic protonated state of active site aspartic acid. These results provide a theoretical prediction of the protonation state of the catalytic aspartic residues for A74707 complex, and may be useful for the evaluation of potential therapeutic targets.
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