分子动力学模拟别构抑制剂Efavirenz对HIV-1逆转录酶的作用

Effect of the Allosteric Inhibitor Efavirenz on HIV-1 Reverse Transcriptase by Molecular Dynamics Simulation

为了理解非核苷类逆转录酶抑制剂(NNRTIs)与HIV-1逆转录酶(RT)的相互作用机制,利用新力场ff12SB对未结合和结合Efavirenz(EFV)逆转录酶的三种RT大分子体系分别进行了100 ns的长时间动力学模拟。通过分析EFV对RT结构的影响、不同残基柔性和不同体系构象的动力学行为等,发现EFV的结合会导致RT结构变化,从而影响RT的活性;证实了EFV的"分子楔"作用;还发现EFV的结合不但引起"拇指关节炎",而且引起轻度"手指关节炎";整个模拟过程中没有出现不同构象间的跃迁,但是无别构分子时的RT张开构象表现出明显的闭合倾向。这些结果有助于理解NNRTIs的抑制机制和RT构象变化的动力学性质。另外,还比较分析了模拟方法对计算结果的影响,对大分子体系的动力学模拟具有重要借鉴意义。

To understand the allosteric modulation dynamics of non-nucleoside reverse transcriptase inhibitors（NNRTIs）, various models and suggestions have been derived from crystallography and simulation. Here, using a new force field, ff12 SB, and GPU parallel computing technology, we performed 100-ns-long molecular dynamics simulations on three reverse transcriptase（RT） systems, one bound to inhibitor Efavirenz（EFV） and the others free. Analyses of the influence of the EFV on the conformation of the RT, flexibility of residues and dynamic behaviors of the systems were conducted. The simulations indicate that EFV binding induces structural distortion of the RT, whereas the configuration of the RT is more stable during dynamics, along with a decreasing extent of motion of the residues. EFV suppresses the flexibility of the thumb subunit and reduces that of most residues in the fingers subdomain as well, suggesting that EFV causes not only the so-called＂thumb arthritis＂but also a slight＂fingers arthritis＂. No conformational transition occurred throughout the entire simulations and the samples maintained their starting conformations, i.e., free RT with a closed conformation stayed in the functional state and EFV-bound RT remained in open conformation. However, EFV-free RT with an initially open conformation exhibited an evident trend toward the closed state. These results agree with the models from experiments, and present a useful insight into the allosteric inhibition mechanism of NNRTIs. In addition, the simulation methodology has been discussed in detail and will be of significance to the computational simulation of large biological molecules.