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对HIV-1蛋白酶催化反应的动态和静电效应

Agnieszka Krzemińska¹, Vicent Moliner², Katarzyna Świderek^1,2

¹Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology , Zeromskiego 116, 90-924 Lodz, Poland.

Journal of the American Chemical Society

|December 10, 2016

概括

这项研究揭示了HIV-1蛋白酶催化机制,确定了一种gem-diol中间体作为关键. 蛋白质动力学影响很小,而活性位点静电学对于抗艾滋病药物设计至关重要.

科学领域:

生物化学
计算化学
结构生物学

背景情况:

艾滋病毒-1蛋白酶 (HIV-1PR) 是艾滋病毒复制的关键酶,也是艾滋病药物开发的主要目标.
了解HIV-1PR的催化机制对于设计有效的抗病毒疗法至关重要.

研究的目的:

探索由HIV-1PR催化的蛋白质分解反应.
调查影响其催化功能的动态和静电效应.
提供对未来抗艾滋病毒/艾滋病药物设计的见解.

主要方法:

使用混合QM/MM的平均力 (PMF) 潜力计算的自由能量表面.
用于QM计算的半实证 (AM1) 和DFT (M06-2X) 级别.
使用蛋白质同位素标记的变异过渡状态理论来研究蛋白质动力学.

主要成果:

最有利的机制涉及一种gem-diol中间体,其分解是限制速度的步骤.
计算的活化自由能量和动态同位素效应 (KIEs) 与实验数据非常相符.
蛋白质动力学对激活自由能量的贡献很小 (<1 kcal·mol-1),而活性位点的静电学则至关重要.

结论:

这项研究阐明了HIV-1 PR的催化机制,强调了二醇中间体的重要性.
活性部位的静电性质对酶的功能至关重要,并代表了药物设计的有希望的途径.
计算结果支持实验观察,并为开发新的抗艾滋病毒药物提供基础.

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