Exploring the Reasons for Decrease in Binding Affinity of HIV-2 Against HIV-1 Protease Complex Using Interaction Entropy Under Polarized Force Field.
Exploring the Reasons for Decrease in Binding Affinity of HIV-2 Against HIV-1 Protease Complex Using Interaction Entropy Under Polarized Force Field.
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利用偏振力场下的相互作用熵探讨 HIV-2 与 HIV-1 蛋白酶复合物结合亲和力降低的原因
DOI：
10.3389/fchem.2018.00380
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发表时间：
2018
影响因子：
5.5
通讯作者：
Duan L
中科院分区：
文献类型：
--
作者：
Cong Y;Li Y;Jin K;Zhong S;Zhang JZH;Li H;Duan L
本研究利用最新发展的结合极化力场的相互作用熵(IE)方法，分析比较了两种HIV-1和HIV-2蛋白水解酶与两种抑制剂(达鲁那韦和氨丙那韦)结合模式的差异。研究了质子化态在两个HIV-2复合体中的功能作用，我们的研究发现B链上Asp25‘的质子化OD1原子是最优的选择。用极化力场结合IE方法计算得到的结合自由能与实验观测结果吻合较好。桥水W301有利于HIV-1复合体的结合，但目前研究中不利于HIV-2复合体的结合。HIV-2复合体的囊腔体积、C-α原子B因子和瓣尖距离均小于HIV-1复合体。这些变化可能导致表面残基的局部重排，最终导致两种类型HIV的不同结合模式。预测的热点残基(Ala28/Ala28‘、Ile50/Ile50’和Ile84/Ile84‘)在四个系统中几乎相同。但是，在HIV-1系统中，Asp30残基对自由能的贡献比在HIV-2系统中更有利。本研究在一定程度上揭示了与HIV-1相比，抑制剂与HIV-2结合亲和力降低的原因，并将为未来设计针对两种类型HIV酶的有效双重抑制剂提供理论指导。
In this study, the differences of binding patterns between two type HIV (HIV-1 and HIV-2) protease and two inhibitors (darunavir and amprenavir) are analyzed and compared using the newly developed interaction entropy (IE) method for the entropy change calculation combined with the polarized force field. The functional role of protonation states in the two HIV-2 complexes is investigated and our study finds that the protonated OD1 atom of Asp25′ in B chain is the optimal choice. Those calculated binding free energies obtained from the polarized force field combined with IE method are significantly consistent with the experimental observed. The bridging water W301 is favorable to the binding of HIV-1 complexes; however, it is unfavorable to the HIV-2 complexes in current study. The volume of pocket, B-factor of Cα atoms and the distance of flap tip in HIV-2 complexes are smaller than that of HIV-1 consistently. These changes may cause localized rearrangement of residues lining their surface and finally result in the different binding mode for the two types HIV. Predicated hot-spot residues (Ala28/Ala28′, Ile50/Ile50′, and Ile84/Ile84′) are nearly same in the four systems. However, the contribution to the free energy of Asp30 residue is more favorable in HIV-1 system than in HIV-2 system. Current study, to some extent, reveals the origin for the decrease in binding affinity of inhibitors against HIV-2 compared with HIV-1 and will provides theoretical guidance for future design of potent dual inhibitors targeting two type HIV protease.
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