用分子对接方法研究HIV-1整合酶与病毒DNA的结合模式

Studies on the Binding Modes of HIV-1 Integrase with Viral DNA via Molecular Docking Method

用分子对接方法研究了HIV-1整合酶(Integrase,IN)二聚体与3′端加工(3′Processing,3′-P)前的8bp及27bp病毒DNA的相互作用,并获得IN与27bp病毒DNA的特异性结合模式.模拟结果表明,IN有特异性DNA结合区和非特异性DNA结合区;IN二聚体B链的K14,R20,K156,K159,K160,K186,K188,R199和A链的K219,W243,K244,R262,R263是IN结合病毒DNA的关键残基;并从结构上解释了能使IN发挥活性的病毒DNA的最小长度是15bp.通过分析结合能发现,IN与DNA稳定结合的主要因素是非极性相互作用,而关键残基与病毒DNA相互识别主要依赖于极性相互作用.模拟结果与实验数据较吻合.

HIV-1 integrase（IN） integrates the viral DNA into the host cell chromosome, however, the bind- ing mode of IN with the viral DNA and the integration mechanism remain unclear. In this paper, molecular docking method was used to investigate the interactions of HIV-1 IN dimer with the 8 bp and 27 bp segments of viral DNA before the 3＇ processing（3＇-P） reaction, and the specific binding mode between IN and its substrate 27 bp segments of viral DNA was obtained. The results show that IN has one specific DNA-binding region and another non-specific DNA-binding region. The key residues for IN dimer binding with viral DNA are K14, R20, K156, K159, K160, K186, K188, R199 residues in chain B and K219, W243, K244, R262, R263 residues in chain A. The explanation for the minimum length of 15 bp viral DNA to activate IN was given on the basis of the docked complex structure. Through the analysis of the binding energy, it was found that non-polar interactions are the principal factor favoring the binding between IN and DNA; whereas, the stable association of viral DNA with the key residues are mainly driven by polar interactions. The simulation results basically agree with the experimental data, which provide us with some structural information for the drug design on the basis of the structure of HIV-1 IN.