博尔茨-ABFE:没有晶体结构的自由能量扰动
Stephan Thaler1,2, Zhiyi Wu2, William G Glass2
1Valence Laboratories, 6666 Rue Saint-Urbain 100, Montréal QC H2S 3H1, Canada.
Journal of chemical theory and computation
|February 12, 2026
概括
自由能量扰动 (FEP) 模拟现在可以在没有实验结构的情况下估计结合亲和力. 新的Boltz-ABFE管道使用预测的蛋白质-连接体复合体来更快地发现药物.
科学领域:
- 计算化学是一种计算化学.
- 药物发现 药物发现
- 结构生物学是结构生物学.
背景情况:
- 自由能量扰动 (FEP) 是绑定亲和度估计的黄金标准.
- FEP的准确性依赖于精确的蛋白质-连接体复杂结构,在药物发现的早期通常无法通过实验获得.
- 现有的方法受限于对实验性晶体结构的需求.
研究的目的:
- 开发一个强大的管道 (博尔茨-ABFE) 绝对结合自由能量 (ABFE) 估计没有实验晶体结构.
- 评估预测的蛋白质 - 连接体复合结构对FEP模拟的有用性.
- 为了在早期药物发现中实现基于结构的亲和度估计.
主要方法:
- 将博尔茨-2结构预测模型与绝对FEP协议集成.
- 开发自动化方法来改进用于分子动力学模拟的预测结构.
- 使用FEP+基准集中的四个蛋白质标验证了Boltz-ABFE管道.
主要成果:
- 博尔茨-2成功地预测了适合FEP的蛋白质连接体复杂结构.
- 自动化结构改进提高了模拟预测模型的质量.
- 博尔茨-ABFE管道准确地估计了无实验结构的多个蛋白质标的ABFE.
结论:
- 博尔茨-ABFE证明了使用预测结构执行FEP模拟的可行性.
- 这种方法显著扩大了FEP在药物发现中的适用性.
- 博尔茨-ABFE通过精确的基于结构的结合亲和度估计,加速早期药物发现.
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