Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT

	Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT
	Shen, LL; Shen, JH; Luo, XM; Cheng, F; Xu, YC; Chen, KX; Arnold, E; Ding, JP; Jiang, HL
刊名	BIOPHYSICAL JOURNAL
	2003
卷号	84 期号:6 页码:3547-3563
通讯作者	Jiang, HL (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res,Ctr Drug Discovery & Desig, Shanghai 200031, Peoples R China.,
英文摘要	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 alpha-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 alpha-APA consists of three phases based on the position of alpha-APA in relation to the entrance of the binding pocket. When alpha-APA is bound in the binding pocket, the hydrophobic interactions between HIV-1 RT and alpha-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 alpha-APA, Tyr-188 forms a strong hydrogen bond with the acylamino group (N14) of alpha-APA. These two residues have very flexible side chains and appear to act as two "flexible clamps" discouraging alpha-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.
学科主题	Biophysics
类目[WOS]	Biophysics
关键词[WOS]	HUMAN-IMMUNODEFICIENCY-VIRUS ; REVERSE-TRANSCRIPTASE INHIBITORS ; DOUBLE-STRANDED DNA ; DRUG-RESISTANCE ; NONNUCLEOSIDE INHIBITORS ; ANGSTROM RESOLUTION ; CRYSTAL-STRUCTURE ; UNBINDING FORCES ; TYPE-1 ; MUTATIONS
收录类别	SCI
语种	英语
WOS记录号	WOS:000183129800006
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/2319]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Shen, LL,Shen, JH,Luo, XM,et al. Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT[J]. BIOPHYSICAL JOURNAL,2003,84(6):3547-3563.
APA	Shen, LL.,Shen, JH.,Luo, XM.,Cheng, F.,Xu, YC.,...&Jiang, HL.(2003).Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT.BIOPHYSICAL JOURNAL,84(6),3547-3563.
MLA	Shen, LL,et al."Steered molecular dynamics simulation on the binding of NNRTI to HIV-1 RT".BIOPHYSICAL JOURNAL 84.6(2003):3547-3563.