Exploring the drug resistance of V32I and M46L mutant HIV-1 protease to inhibitor TMC114: flap dynamics and binding mechanism.
Exploring the drug resistance of V32I and M46L mutant HIV-1 protease to inhibitor TMC114: flap dynamics and binding mechanism.
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DOI：
10.1016/j.jmgm.2014.11.003
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发表时间：
2015-03
影响因子：
2.9
通讯作者：
Wang, Yixuan
中科院分区：
文献类型：
--
作者：
Meher, Biswa Ranjan;Wang, Yixuan
关键词：
HIV-1蛋白酶（HIV-1-pr）的抑制剂通常仅与蛋白酶的活性位点结合。然而，对于一些突变体，如V32 I和M46 L，TMC 114不仅可以结合到活性腔，还可以结合到柔性翼的凹槽。尽管第二个结合位点表明药物对HIV-1-pr的效率更高，但由于突变引起的HIV-1-pr的耐药性不容忽视，这促使我们研究耐药性的分子机制和TMC 114与HIV-1-pr的双结合行为。用全原子分子动力学（MD）模拟研究了V32 I和M46 L突变体。20 ns MD模拟显示了抑制剂结合WT和突变蛋白酶的许多迷人的效果。MM-PBSA计算解释了与WT相比，M46 L和V32 I突变体不利的结合自由能。对于单一结合，较低的结合亲和力可归因于V32 I-1 T和M46 L-1 T两者的熵损失。尽管TMC 114与flap的第二次结合确实增加了突变体（V32 I-2 T和M46 L-2 T）的结合能，但相当大的熵损失导致较低的结合吉布斯自由能。因此，片状区域中的TMC 114结合对系统结合亲和力的总增益没有多大帮助，这一点从本研究中得到了验证，从而验证了实验。
Inhibitors of HIV-1 protease (HIV-1-pr) generally only bind to the active site of the protease. However, for some mutants such as V32I and M46L the TMC114 can bind not only to the active cavity also to the groove of the flexible flaps. Although the second binding site suggests the higher efficiency of the drug against HIV-1-pr, the drug resistance in HIV-1-pr due to mutations cannot be ignored, which prompts us to investigate the molecular mechanisms of drug resistance and behavior of double bound TMC114 to HIV-1-pr. The conformational dynamics of HIV-1-pr and the binding of TMC114 to the WT, V32I and M46L mutants were investigated with all-atom molecular dynamic (MD) simulation. The 20 ns MD simulation shows many fascinating effects of the inhibitor binding to the WT and mutant proteases. MM-PBSA calculations explain the binding free energies unfavorable for the M46L and V32I mutants as compared to the WT. For the single binding the less binding affinity can be attributed to the entropic loss for both V32I-1T and M46L-1T. Although the second binding of TMC114 with flap does increase binding energy for the mutants (V32I-2T and M46L-2T), the considerable entropy loss results in the lower binding Gibbs free energies. Thus, binding of TMC114 in the flap region doesn't help much in the total gain in binding affinity of the system, which was verified from this study and thereby validating experiments.
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影响因子：
2.9
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Wang, Yixuan
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