Investigation of the Protonated State of HIV-1 Protease Active Site

Bulletin of the Korean chemical society

Chul Kyu Han¹  Kyoung Tai No¹  Ky-Youb Nam¹  Soon Gil Ahn¹  Byung Ha Chang¹ 

关键词: HIV-1 protease;    Protonated state;    ab initio;    SCI-PCM SCRF;    Free energy perturbation;   

DOI  :  

学科分类：化学（综合）

来源: Korean Chemical Society

【 摘 要 】

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.

【 授权许可】

Unknown