Centre for Computational Science, Department of Chemistry, University College London, London, WC1H 0AJ, UK.
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Biology (Basel). 2012 Jul 26;1(2):222-44. doi: 10.3390/biology1020222.
HIV-1 Reverse Transcriptase (RT) is a multifunctional enzyme responsible for the transcription of the RNA genome of the HIV virus into DNA suitable for incorporation within the DNA of human host cells. Its crucial role in the viral life cycle has made it one of the major targets for antiretroviral drug therapy. The Non-Nucleoside RT Inhibitor (NNRTI) class of drugs binds allosterically to the enzyme, affecting many aspects of its activity. We use both coarse grained network models and atomistic molecular dynamics to explore the changes in protein dynamics induced by NNRTI binding. We identify changes in the flexibility and conformation of residue Glu396 in the RNaseH primer grip which could provide an explanation for the acceleration in RNaseH cleavage rate observed experimentally in NNRTI bound HIV-1 RT. We further suggest a plausible path for conformational and dynamic changes to be communicated from the vicinity of the NNRTI binding pocket to the RNaseH at the other end of the enzyme.
HIV-1 逆转录酶（RT）是一种多功能酶，负责将 HIV 病毒的 RNA 基因组转录成适合整合到人宿主细胞 DNA 中的 DNA。它在病毒生命周期中的关键作用使其成为抗逆转录病毒药物治疗的主要靶点之一。非核苷类逆转录酶抑制剂（NNRTI）类药物通过变构方式与酶结合，影响其许多活性。我们使用粗粒度网络模型和原子分子动力学来探索 NNRTI 结合引起的蛋白质动力学变化。我们确定了 RNaseH 引物夹中残基 Glu396 的柔韧性和构象的变化，这可以为实验中观察到的 NNRTI 结合的 HIV-1 RT 中 RNaseH 切割速率的加速提供解释。我们进一步提出了一种可能的构象和动态变化途径，从 NNRTI 结合口袋附近传递到酶的另一端的 RNaseH。
