Hybrid QM/MM Free-Energy Evaluation of Drug-Resistant Mutational Effect on the Binding of an Inhibitor Indinavir to HIV-1 Protease
Hybrid QM/MM Free-Energy Evaluation of Drug-Resistant Mutational Effect on the Binding of an Inhibitor Indinavir to HIV-1 Protease
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DOI：
10.1021/acs.jcim.1c01193
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发表时间：
2022-03-14
影响因子：
5.6
通讯作者：
Hayashi，Shigehiko
中科院分区：
文献类型：
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作者：
Taguchi，Masahiko;Oyama，Ryo;Hayashi，Shigehiko
人免疫缺陷病毒-1（HIV-1）蛋白酶是HIV复制所必需的同源二聚体天冬氨酸蛋白酶。HIV-1蛋白酶是抗逆转录病毒治疗药物发现中的靶蛋白，并且已经开发了过渡态类似物的各种抑制剂分子。然而，出现了严重的耐药突变体。为了了解耐药的分子机制，需要准确检查突变对配体结合和酶活性的影响。在这里，我们提出了一个分子模拟研究的配体结合的茚地那韦，一种有效的过渡态类似物抑制剂，野生型蛋白质和V82 T/I84 V耐药突变体的HIV-1蛋白酶。我们采用了一种混合从头算量子力学/分子力学（QM/MM）自由能优化技术，该技术结合了高精度的QM描述的配体分子和它的相互作用与统计充分的构象采样的MM蛋白质环境的长时间分子动力学模拟。通过自由能计算的质子化状态的催化基团的结合口袋和配体结合亲和力的变化后的突变，我们成功地再现了实验观察到的显着降低的结合亲和力后的耐药突变，并阐明了潜在的分子机制。本研究通过直接定量比较配体结合和酶促反应，以相同的准确度，为了解耐药的分子机制开辟了道路。
A human immunodeficiency virus-1 (HIV-1) protease is a homodimeric aspartic protease essential for the replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analogues have been developed. However, serious drug-resistant mutants have emerged. For understanding the molecular mechanism of the drug resistance, an accurate examination of the impacts of the mutations on ligand binding and enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of indinavir, a potent transition state analogue inhibitor, to the wild-type protein and a V82T/I84V drug-resistant mutant of the HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free-energy optimization technique which combines a highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of the MM protein environment by long-time molecular dynamics simulations. Through the free-energy calculations of protonation states of catalytic groups at the binding pocket and of the ligand-binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug resistance through the direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.