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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 24, Number 6
BKCSDE 24(6)
June 20, 2003 

Investigation of the Protonated State of HIV-1 Protease Active Site
Ky-Youb Nam, Byung Ha Chang, Chul Kyu Han, Soon Gil Ahn, Kyoung Tai No
HIV-1 protease, Protonated state, ab initio, SCI-PCM SCRF, Free energy perturbation
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, Asp125), formamide (amide bond of Thr26/Gly27, Thr126/ 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 DEbind, 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 I Asp125 ? AspH25 I Asp125, ii) Asp25 I Asp125 ? Asp25 I AspH125, iii) AspH25 I Asp125 ? AspH25 I 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.
817 - 823
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