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* Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P. R. China; Key Laboratory of Proteomics, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P. R. China; and Center for Advanced Biotechnology and Medicine (CABM) and Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey 08854 USA
Correspondence: Address reprint requests to Profs. Hualiang Jiang, Tel.: 86-21-50807188; Fax: 86-21-50807088; E-mail: jiang{at}iris3.simm.ac.cn; or Jianhua Shen, Tel.: 86-21-50807188; Fax: 86-21-50807088; E-mail: jhshen{at}iris3.simm.ac.cn; or Jianping Ding, Tel.: 86-21-64331914; Fax: 86-21-64338357; E-mail: ding{at}sunm.shcnc.ac.cn.
HIV-1 reverse transcriptase (RT) is the primary target for anti-AIDS chemotherapy. Nonnucleoside RT inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 RT. The binding and unbinding processes of 
-APA, an NNRTI, have been studied using nanosecond conventional molecular dynamics and steered molecular dynamics simulations. The simulation results show that the unbinding process of -APA consists of three phases based on the position of -APA in relation to the entrance of the binding pocket. When -APA is bound in the binding pocket, the hydrophobic interactions between HIV-1 RT and -APA dominate the binding; however, the hydrophilic interactions (both direct and water-bridged hydrogen bonds) also contribute to the stabilizing forces. Whereas Tyr-181 makes significant hydrophobic interactions with -APA, Tyr-188 forms a strong hydrogen bond with the acylamino group (N14) of -APA. These two residues have very flexible side chains and appear to act as two "flexible clamps" discouraging -APA to dissociate from the binding pocket. At the pocket entrance, two relatively inflexible residues, Val-179 and Leu-100, gauge the openness of the entrance and form the bottleneck of the inhibitor-unbinding pathway. Two special water molecules at the pocket entrance appear to play important roles in inhibitor recognition of binding and unbinding. These water molecules form water bridges between the polar groups of the inhibitor and the residues around the entrance, and between the polar groups of the inhibitor themselves. The water-bridged interactions not only induce the inhibitor to adopt an energetically favorable conformation so the inhibitor can pass through the pocket entrance, but also stabilize the binding of the inhibitor in the pocket to prevent the inhibitor's dissociation. The complementary steered molecular dynamics and conventional molecular dynamics simulation results strongly support the hypothesis that NNRTIs inhibit HIV-1 RT polymerization activity by enlarging the DNA-binding cleft and restricting the flexibility and mobility of the p66 thumb subdomain that are believed to be essential during DNA translocation and polymerization.
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