扩展自动化的多构造体联体模拟到宏循环和片段
Jessica Flowers1, Nathaniel Echols1, Galen Correy1
1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.
bioRxiv : the preprint server for biology
|October 10, 2024
概括
连接体可以以多种形状 (形状) 存在,即使在与蛋白质结合之后. 改进的软件,qFit-ligand,现在使用增强的采样更好地模拟这些多样化的连接体形状,帮助药物设计.
科学领域:
- 结构生物学是结构生物学.
- 计算化学是一种计算化学.
- 药物发现 药物发现
背景情况:
- 小分子连接体在溶液中表现出形状灵活性,并且可以在蛋白质结合时保持一定灵活性.
- 当前的结构模型通常只代表单个连接体构造,可能忽略了重要的构造异质性.
- 以前用于建模连接体构造的计算方法存在局限性,包括非物理结果和无法处理像宏循环这样的复杂分子.
研究的目的:
- 引入一个改进版的qFit-ligand,具有增强的 conformational 采样能力.
- 扩展qFit-ligand用于分析高通量X射线晶体学数据中的替代联体构造.
- 为了更好的药物设计,更好地描述联结蛋白结构中的残余构造异质性.
主要方法:
- 在qFit-ligand中使用RDKit程序实施了随机构造采样.
- 扩展了qFit-ligand来处理来自碎片选的PanDDA修改密度图.
- 通过将其与电子密度相匹配并对现有模型进行扭曲应变的评估,评估了新的qFit-ligand版本.
主要成果:
- 增强的qFit-ligand成功地为小分子和宏循环采样了更广泛的低能形态.
- 改进后的软件显示出与以前的版本和单个调整器模型相比,更好地适应电子密度和减少扭曲应变.
- qFit-ligand现在可以有效地识别来自高通量片段选实验的数据中的替代性联体构造.
结论:
- 改进的qFit-ligand在结构模型中提供了更准确的对联体结构异质性的表示.
- 这种模拟多种连接体构造的增强能力为治疗剂的合理设计提供了宝贵的见解.
- 这些进展有助于更深入地了解连接体-蛋白相互作用和构造动态.
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