Mechanistic study of HIV-1 reverse transcriptase at the active site based on QM/MM method

被引:9
作者
Rungrotmongkol, T [1 ]
Hannongbua, S
Mulholland, A
机构
[1] Kasetsart Univ, Fac Sci, Dept Chem, Bangkok 10900, Thailand
[2] Univ Bristol, Sch Chem, Ctr Computat Chem, Bristol, Avon, England
基金
英国工程与自然科学研究理事会;
关键词
HIV-1; RT; active site; DNA polymerization; QM/MM method;
D O I
10.1142/S0219633604001252
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
HIV-1 RT catalyses the reverse transcription of viral genetic material (RNA) into double-stranded DNA, and is an important target of antiviral therapy in the treatment of AIDS. Better understanding of the structure, mechanism and functional role of residues involved in the resistance of HIV-1 RT against nucleoside-analog drugs may assist in the development of improved inhibitors, and also in understanding the effects of genetic variation on RT specificity and activity. In this study, firstly, molecular dynamics simulations (with CHARMM27) have been used to investigate binding interactions at the active site and the conformational behavior of the enzyme, then, mechanisms of deprotonation and DNA polymerization reactions have been modelled by the QM/MM method. A combined quantum mechanical and molecular mechanical (QM/MM) method (AM1/CHARMM) has been used to study the triphosphate substrate and the active site of HIV-1 reverse transcriptase complex structure, a virally-encoded enzyme. Free energy profiles for the reaction are also calculated. The obtained results provide important insight into the mechanistic activity of HIV-1 RT.
引用
收藏
页码:491 / 500
页数:10
相关论文
共 50 条
  • [1] Active site dynamics and combined quantum mechanic s/molecul ar mechanics (QM/MM) modelling of a HIV-1 reverse transcriptase/DNA/dTTP complex
    Rungrotmongkol, Thanyada
    Mulholland, Adrian J.
    Hannongbua, Supa
    JOURNAL OF MOLECULAR GRAPHICS & MODELLING, 2007, 26 (01) : 1 - 13
  • [2] Mechanistic studies of incorporation of activated Islatravir by HIV-1 reverse transcriptase mutants
    Zalenski, Nikita
    Suo, Zucai
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2024, 300 (03) : S164 - S164
  • [3] Active site binding modes of dimeric phloroglucinols for HIV-1 reverse transcriptase, protease and integrase
    Gupta, Pawan
    Kumar, Rajender
    Garg, Prabha
    Singh, Inder Pal
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (15) : 4427 - 4431
  • [4] Developing and Evaluating Inhibitors against the RNase H Active Site of HIV-1 Reverse Transcriptase
    Boyer, Paul L.
    Smith, Steven J.
    Zhao, Xue Zhi
    Das, Kalyan
    Gruber, Kevin
    Arnold, Eddy
    Burke, Terrence R., Jr.
    Hughes, Stephen H.
    JOURNAL OF VIROLOGY, 2018, 92 (13)
  • [5] Novel HIV-1 reverse transcriptase inhibitors
    Jochmans, Dirk
    VIRUS RESEARCH, 2008, 134 (1-2) : 171 - 185
  • [6] HIV-1 non-nucleoside reverse transcriptase inhibitors
    Högberg, M
    Morrison, I
    EXPERT OPINION ON THERAPEUTIC PATENTS, 2000, 10 (08) : 1189 - 1199
  • [7] Argentine plant extracts active against polymerase and ribonuclease H activities of HIV-1 reverse transcriptase
    Hnatyszyn, O
    Broussalis, A
    Herrera, G
    Muschietti, L
    Coussio, J
    Martino, V
    Ferraro, G
    Font, M
    Monge, A
    Martínez-Irujo, JJ
    Sanromán, M
    Cuevas, MT
    Santiago, E
    Lasarte, JJ
    PHYTOTHERAPY RESEARCH, 1999, 13 (03) : 206 - 209
  • [8] Effect of tRNA on the Maturation of HIV-1 Reverse Transcriptase
    Ilina, Tatiana V.
    Slack, Ryan L.
    Elder, John H.
    Sarafianos, Stefan G.
    Parniak, Michael A.
    Ishima, Rieko
    JOURNAL OF MOLECULAR BIOLOGY, 2018, 430 (13) : 1891 - 1900
  • [9] SPECIFIC HIV-1 REVERSE-TRANSCRIPTASE INHIBITORS
    DEBYSER, Z
    PAUWELS, R
    ANDRIES, K
    DE CLERCQ, E
    JOURNAL OF ENZYME INHIBITION, 1992, 6 (01): : 47 - 53
  • [10] Oligonucleotide inhibitors of HIV-1 integrase efficiently inhibit HIV-1 reverse transcriptase
    S. P. Korolev
    T. S. Zatsepin
    M. B. Gottikh
    Russian Journal of Bioorganic Chemistry, 2017, 43 : 135 - 139