Bulletin of the Korean chemical society | |
Investigation of the Protonated State of HIV-1 Protease Active Site | |
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
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO201912010238971ZK.pdf | 535KB | download |