Binding of single walled carbon nanotube to WT and mutant HIV-1 proteases: analysis of flap dynamics and binding mechanism.
Binding of single walled carbon nanotube to WT and mutant HIV-1 proteases: analysis of flap dynamics and binding mechanism.
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DOI：
10.1016/j.jmgm.2012.10.001
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发表时间：
2012-09
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：
目前治疗的大多数HIV-1蛋白酶（HIV-PR）抑制剂都容易发生与耐药相关的突变。因此，有必要寻找有效的替代药物来对抗耐药性。在目前的研究中，我们已经测试了单壁碳纳米管（SWCNT）作为抑制剂在野生型（WT），以及在三个主要的突变体（I50 VPR，V82 APR和I84 VPR）的HIV-1-PR通过对接单壁碳纳米管的活性位点区域，然后进行全原子MD模拟的复合物。具有20 ns轨迹的HIV-PR的构象动力学表明，单壁碳纳米管可以有效地结合到HIV-1-PR活性位点并调节皮瓣动力学，例如保持皮瓣-皮瓣关闭。为了深入了解结合亲和力，我们还对四种HIV-PR/SWCNT复合物进行了基于MM-PBSA的结合自由能计算。观察到，尽管SWCNT和HIV-PR之间的结合由于突变而降低，但SWCNT与HIV-PR的结合比最有效的HIV-I-PR抑制剂TMC 114强3-5倍。值得注意的是，结合能高于1 kcal/mol的显着相互作用集中在瓣和活性区域，这有利于闭合瓣-瓣并使HIV-PR的活性残基失活。HIV-PR和SWCNT的瓣动力学和结合强度信息可以帮助设计基于SWCNT的HIV-1-PR抑制剂。
Most of the currently treated HIV-1 protease (HIV-PR) inhibitors have been prone to suffer from the mutations associated drug resistance. Therefore, it is necessary to search for potent alternatives against the drug resistance. In the current study we have tested the single-walled carbon nanotube (SWCNT) as an inhibitor in wild type (WT) as well as in three primary mutants (I50VPR, V82APR and I84VPR) of the HIV-1-PR through docking the SWCNT in the active site region, and then performed all-atom MD simulations for the complexes. The conformational dynamics of HIV-PR with a 20 ns trajectory reveals that the SWCNT can effectively bind to the HIV-1-PR active site and regulate the flap dynamics such as maintaining the flap-flap closed. To gain an insight into the binding affinity, we also performed the MM-PBSA based binding free energy calculations for the four HIV-PR/SWCNT complexes. It was observed that, although the binding between the SWCNT and the HIV-PR decreases due to the mutations, the SWCNTs bind to the HIV-PRs 3–5 folds stronger than the most potent HIV-1-PR inhibitor, TMC114. Remarkably, the significant interactions with binding energy higher than 1 kcal/mol focus on the flap and active regions, which favors closing flap-flap and deactivating the active residues of the HIV-PR. The flap dynamics and binding strength information for HIV-PR and SWCNTs can help design SWCNT-based HIV-1-PR inhibitors.
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