Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir.
Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir.
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耐药突变对 HIV-1 蛋白酶动态特性的影响以及 Amprenavir 和 Darunavir 的抑制作用。
DOI：
10.1038/srep10517
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发表时间：
2015-05-27
影响因子：
4.6
通讯作者：
Zhu W
中科院分区：
文献类型：
--
作者：
Yu Y;Wang J;Shao Q;Shi J;Zhu W
采用分子动力学模拟方法研究了野生型HIV-1蛋白酶及其两种多药耐药变异体（Flap +（L10 I/G48 V/I54 V/V82 A）和Act（V82 T/I84 V））的动力学性质以及它们与APV和DRV抑制剂的结合。flap和80 s环残基（主要是I50-I84'和I50'-I84）之间的疏水相互作用对维持HIV-1蛋白酶的封闭构象起重要作用。Act变异体中的双突变削弱了疏水相互作用，导致apo Act从封闭构象转变为半开放构象。APV或DRV通过疏水和氢键相互作用与HIV-1蛋白酶结合。抑制剂的疏水作用主要针对I50（I50 '）、I84（I84'）和V82（V82 '）残基，这些残基形成疏水核心簇以进一步稳定瓣的闭合构象，氢键作用主要集中在HIV-1蛋白酶的活性位点。两种蛋白酶-抑制剂相互作用的组合变化与观察到的耐药突变相关。本研究揭示了突变对HIV-1蛋白酶动力学的影响以及APV和DRV抑制HIV-1蛋白酶的微观机制，为设计更有效的HIV-1蛋白酶抑制剂提供了有用的信息。
Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The hydrophobic interactions between flap and 80 s (80’s) loop residues (mainly I50-I84’ and I50’-I84) play an important role in maintaining the closed conformation of HIV-1 protease. The double mutation in Act variant weakens the hydrophobic interactions, leading to the transition from closed to semi-open conformation of apo Act. APV or DRV binds with HIV-1 protease via both hydrophobic and hydrogen bonding interactions. The hydrophobic interactions from the inhibitor is aimed to the residues of I50 (I50’), I84 (I84’), and V82 (V82’) which create hydrophobic core clusters to further stabilize the closed conformation of flaps, and the hydrogen bonding interactions are mainly focused with the active site of HIV-1 protease. The combined change in the two kinds of protease-inhibitor interactions is correlated with the observed resistance mutations. The present study sheds light on the microscopic mechanism underlying the mutation effects on the dynamics of HIV-1 protease and the inhibition by APV and DRV, providing useful information to the design of more potent and effective HIV-1 protease inhibitors.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
分解耐药突变的能量影响：HIV-1 蛋白酶与 DRV 结合的例子。
DOI：
10.1007/978-1-61779-465-0_32
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Cai Y;Schiffer C
通讯作者：
Schiffer C
HIV-1蛋白酶皮瓣区域中抗药性突变的合作作用。
影响因子：
4
作者：
Foulkes-Murzycki, Jennifer E.;Rosi, Christina;Yilmaz, Nese Kurt;Shafer, Robert W.;Schiffer, Celia A.
通讯作者：
Schiffer, Celia A.
影响因子：
5.5
作者：
Cai, Yufeng;Schiffer, Celia A.
通讯作者：
Schiffer, Celia A.
影响因子：
5.5
作者：
Cai, Yufeng;Myint, Wazo;Paulsen, Janet L.;Schiffer, Celia A.;Ishima, Rieko;Yilmaz, Nese Kurt
通讯作者：
Yilmaz, Nese Kurt