Structural and dynamical properties of different protonated states of mutant HIV-1 protease complexed with the saquinavir inhibitor studied by molecular dynamics simulations
Structural and dynamical properties of different protonated states of mutant HIV-1 protease complexed with the saquinavir inhibitor studied by molecular dynamics simulations
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DOI：
10.1016/j.jmgm.2006.01.004
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发表时间：
2006-11-01
影响因子：
2.9
通讯作者：
Hannongbua, Supot
中科院分区：
文献类型：
--
作者：
Aruksakunwong, Ornjira;Wittayanarakul, Kitiyaporn;Hannongbua, Supot
为了理解耐药性的基础，特别是HIV-1 PR的耐药性，在明确的水溶液中，用三种质子化状态，Asp 25和Asp 25 '上的双质子化（Di-pro）和每个Asp残基上的单质子化（Mono-25和Mono-25'），对HIV-1 PR突变体G48 V与沙奎那韦（SQV）复合进行了三种分子动力学（MD）模拟。对于所有三种状态，沙奎那韦和HIV-1 PR之间的氢键仅在两个区域形成，皮瓣和活性位点。结果表明，SQV在Mono-25态下的P2亚位构象与其它两种状态下的构象有很大的不同。观察到从野生型的最佳结构旋转约177度，P2与瓣状残基（Va 148）之间的氢键被破坏，而发现与三个残基（Asp 29、Gly 27和Asp 30）的间接氢键。在络合能方面，Mono-25态的相互作用能为-37.3 kcal/mol，显著低于Mono-25'和Di-pro态的相互作用能，分别为-30.7和-10.7 kcal/mol。还发现Asp 25处的质子化导致催化二元体中更好的排列，即，Asp 25-Asp 25 '相互作用能Mono-25为-8.8kcal/mol，明显低于Mono-25'的-2.6kcal/mol。上述数据提示我们，催化区域的相互作用应作为标准，以提高药物设计和药物筛选的能力，而不是使用总的抑制剂/酶相互作用。(c)2006年爱思唯尔公司All rights reserved.
To understand the basis of drug resistance, particularly of the HIV-1 PR, three molecular dynamics (MD) simulations of HIV-1 PR mutant species, G48V, complexed with saquinavir (SQV) in explicit aqueous solution with three protonation states, diprotonation on Asp25 and Asp25' (Di-pro) and monoprotonation on each Asp residue (Mono-25 and Mono-25'). For all three states, H-bonds between saquinavir and HIV-1 PR were formed only in the two regions, flap and active site. It was found that conformation of P2 subsite of SQV in the Mono-25 state differs substantially from the other two states. The rotation about 177 degrees' from the optimal structure of the wild type was observed, the hydrogen bond between P2 and the flap residue (Va148) was broken and indirect hydrogen bonds with the three residues (Asp29, Gly27, and Asp30) were found instead. In terms of complexation energies, interaction energy of -37.3 kcal/mol for the Mono-25 state is significantly lower than those of -30.7 and - 10.7 kcal/mol for the Mono-25' and Di-pro states, respectively. It was found also that protonation at the Asp25 leads to a better arrangement in the catalytic dyad, i.e., the Asp25-Asp25' interaction energy of -8.8 kcal/mol of the Mono-25 is significantly lower than that of -2.6 kcal/mol for the Mono-25' state. The above data suggest us to conclude that interaction in the catalytic area should be used as criteria to enhance capability in drug designing and drug screening instead of using the total inhibitor/enzyme interaction. (c) 2006 Elsevier Inc. All rights reserved.