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

Abstract:

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, ff12SB, 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.

Key words: HIV-1 reverse transcriptase, Nonnucleoside reverse transcriptase inhibitor, Allosteric inhibitor, Molecular dynamics simulation, Conformation