耐药进化驱动HIV-1蛋白酶瓣区动力学的不稳定。

IF 2.4 Q3 BIOPHYSICS
Madhusudan Rajendran, Maureen C Ferran, Leora Mouli, Gregory A Babbitt, Miranda L Lynch
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引用次数: 1

摘要

HIV-1蛋白酶是人类免疫缺陷病毒感染和获得性免疫缺陷综合征联合药物治疗的几个常见关键靶点之一。在疾病的发展过程中,个别患者由于联合药物治疗靶向的病毒蛋白发生突变热点而产生耐药性。最近发现,耐药突变积聚在HIV-1蛋白酶的“皮瓣区”,这是一个在侵袭和感染宿主细胞过程中参与非特异性多肽结合的关键动态区域。在这项研究中,我们利用机器学习辅助的比较分子动力学,在单氨基酸位点分辨率下进行,研究野生型和常见耐药版本的主要蛋白酶在功能二聚化和药物结合过程中发生的动态变化。我们还使用多智能体机器学习模型来识别在猿类和猫科动物蛋白酶同源物中保存的HIV-1主要蛋白酶的保守动态。我们发现皮瓣区域一个关键的保守功能位点,一个控制皮瓣动力学的溶剂暴露异亮氨酸(Ile50)被耐药性突变功能靶向,导致放大的分子动力学影响皮瓣区域保持药物的功能能力。我们得出的结论是,通过设计针对蛋白酶区域的药物,可以实现更好的长期患者预后,这些区域较少依赖于具有大功能结合效应的单个位点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Evolution of drug resistance drives destabilization of flap region dynamics in HIV-1 protease.

Evolution of drug resistance drives destabilization of flap region dynamics in HIV-1 protease.

Evolution of drug resistance drives destabilization of flap region dynamics in HIV-1 protease.

Evolution of drug resistance drives destabilization of flap region dynamics in HIV-1 protease.

The HIV-1 protease is one of several common key targets of combination drug therapies for human immunodeficiency virus infection and acquired immunodeficiency syndrome. During the progression of the disease, some individual patients acquire drug resistance due to mutational hotspots on the viral proteins targeted by combination drug therapies. It has recently been discovered that drug-resistant mutations accumulate on the "flap region" of the HIV-1 protease, which is a critical dynamic region involved in nonspecific polypeptide binding during invasion and infection of the host cell. In this study, we utilize machine learning-assisted comparative molecular dynamics, conducted at single amino acid site resolution, to investigate the dynamic changes that occur during functional dimerization and drug binding of wild-type and common drug-resistant versions of the main protease. We also use a multiagent machine learning model to identify conserved dynamics of the HIV-1 main protease that are preserved across simian and feline protease orthologs. We find that a key conserved functional site in the flap region, a solvent-exposed isoleucine (Ile50) that controls flap dynamics is functionally targeted by drug resistance mutations, leading to amplified molecular dynamics affecting the functional ability of the flap region to hold the drugs. We conclude that better long-term patient outcomes may be achieved by designing drugs that target protease regions that are less dependent upon single sites with large functional binding effects.

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来源期刊
Biophysical reports
Biophysical reports Biophysics
CiteScore
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