外膜嵌入的多糖分泌孔氨酸的分子动力学揭示了关闭的静态表面门,可通过虚拟碎片查来准药物热点识别
Tanos C C França1,2,3,4, Fares Saïdi1,2, Alain Ajamian5
1Institut National de la Recherche Scientifique (INRS), Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Institut Pasteur International Network, Laval, QC H7V 1B7, Canada.
ACS omega
|March 25, 2024
概括
我们开发了一种分子动力学协议,用于研究细菌外膜. 这种方法验证了蛋白质模型,并揭示了抑制多糖分泌的潜在药物标.
科学领域:
- 结构生物学和生物信息学
- 计算生物物理学和分子建模.
背景情况:
- 基于神经网络的蛋白质结构预测方面的进步 (例如,AlphaFold2) 在整体膜蛋白中表现出色,但忽视了膜效应.
- 之前的研究已经在Myxococcus xanthus中确定了18-β链外膜毛孔 (WzpX,WzpS,WzpB),但缺乏关于它们的动态行为和失活策略的数据.
研究的目的:
- 开发和验证一个分子动力学 (MD) 协议,以评估神经网络衍生的整体膜蛋白模型的稳定性和循环动力学.
- 为了研究在不对称的外膜双层内WzpX/S/B porin循环域的动态行为.
- 为了确定潜在的可用药物的部位,以抑制多糖分泌途径.
主要方法:
- 集成CHARMM-GUI和分子操作环境 (MOE) 以快速模拟设置和分析MD模拟.
- 模拟嵌入不对称的外膜双层中的WzpX,WzpS和WzpBβ-桶蛋白模型.
- 虚拟选碎片库对已识别的空洞进行选,以找到潜在的抑制剂.
主要成果:
- 通过结合膜效应,MD协议成功验证了基于神经网络的蛋白质模型.
- 模拟显示了细胞外WzpX/S/B循环在没有外部刺激的情况下的最小运动,并确定了可用药物的腔.
- 虚拟选确定了碎片结合热点和关键残留物,确定了多糖分泌的潜在抑制剂.
结论:
- 开发的MD协议为在膜环境中验证和分析积分膜蛋白模型提供了强大的方法.
- 鉴定了可用药物的空洞和潜在的抑制剂,为开发阻断细菌多糖分泌的治疗方法提供了一个有希望的途径.
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