进化序列和HIV耐药性的表观起源的结构基础
bioRxiv : the preprint server for biology
|May 14, 2025
概括
突变效应取决于序列背景的表观性,驱动人类免疫缺陷病毒 (HIV) 耐药性. 这些相互作用是蛋白质稳定性的内在因素,而不是药物结合,指导耐药性进化.
科学领域:
- 病毒学 病毒学
- 生物物理学的生物物理.
- 计算生物学 计算生物学
背景情况:
- 人类免疫缺陷病毒 (HIV) 的耐药性损害了抗逆转录病毒疗法 (ART) 的有效性.
- 突变的上下文依赖效应,即表观性,对于在ART选择下塑造HIV的健康格局至关重要.
- 艾滋病毒抗药性突变 (DRM) 中表观症的生物物理基础尚未完全理解.
研究的目的:
- 调查导致艾滋病毒耐药性的表皮性相互作用的起源.
- 要确定这些相互作用是否与蛋白质特性固有,还是由于药物结合而产生的.
主要方法:
- 利用基于患者衍生的HIV-1序列的Potts统计能量模型来创建计算双突变周期.
- 在三个主要的HIV药物向酶中对所有观察到的突变进行了对对的表达.
- 进行了分子动力学自由能量模拟,以分析强烈的表观相互作用的结构基础.
主要成果:
- 在抵抗相关位置的突变之间观察到最强的表皮性影响,在ART期间经常发生突变.
- 分子动力学模拟显示,表皮症主要来自于对蛋白质稳定性和折叠的合作作用.
- 这些效应是蛋白质突变格局的内在结果.
结论:
- 艾滋病毒耐药性通过突变在内在合的部位进化,这些部位合作减轻个体DRM的健康成本.
- 这种机制允许病毒通过利用固有的蛋白质特性来逃避药物压力.
- 这项研究为基于表观性相互作用网络预测抗性演变提供了基础.
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