物理化学学报Issue(2)：436-444,9.DOI:10.3866/PKU.WHXB201511302
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
摘要
Abstract
To understand the al osteric modulation dynamics of non-nucleoside reverse transcriptase inhibitors (NNRTIs), various models and suggestions have been derived from crystal ography and simulation. Here, using a new force field, ff12SB, and GPU paral el 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 wel , suggesting that EFV causes not only the so-cal ed“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 initial y 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 al osteric inhibition mechanism of NNRTIs. In addition, the simulation methodology has been discussed in detail and wil be of significance to the computational simulation of large biological molecules.关键词
HIV-I逆转录酶/逆转录酶抑制剂/别构抑制剂/分子动力学模拟/构象Key words
HIV-1 reverse transcriptase/Nonnucleoside reverse transcriptase inhibitor/Al osteric inhibitor/Molecular dynamics simulation/Conformation分类
化学化工引用本文复制引用
孟现美,张少龙,张庆刚..分子动力学模拟别构抑制剂Efavirenz对HIV-1逆转录酶的作用[J].物理化学学报,2016,(2):436-444,9.基金项目
The project was supported by the National Natural Science Foundation of China (11274206).国家自然科学基金(11274206)资助项目 （11274206）
