在马丁尼3力场中优化了蛋白质辅助物相互作用
Tobias M Prass1, Kresten Lindorff-Larsen2, Patrick Garidel3
1Center for Theoretical Chemistry, Ruhr University Bochum, D-44780 Bochum, Germany.
Journal of chemical information and modeling
|March 25, 2025
概括
这项研究改进了高度抗体药物的粗粒度模拟,通过对阿金和谷氨酸酸辅助剂的马蒂尼3力场进行重新参数化. 这增强了人们对这些辅助剂如何稳定治疗蛋白质的理解.
科学领域:
- 计算化学计算化学
- 生物物理学的生物物理.
- 制药科学 制药科学
背景情况:
- 高度单克隆抗体 (mAb) 配方面临着可溶性和颗粒形成的挑战.
- 像氨酸和谷氨酸这样的助剂可以提高蛋白质的稳定性,但需要详细的分子理解.
- 全原子分子动力学 (MD) 模拟提供了洞察力,但对于大型系统而言,计算能力有限.
研究的目的:
- 扩展马丁尼3粗粒度力场,以准确建模mAb配方中的蛋白质辅助剂相互作用.
- 开发和验证使用治疗 mAb Fab 域的氨酸和谷氨酸辅助剂的新参数.
主要方法:
- 开发了一种新的全原子到粗粒度映射氨基酸辅助剂的新的全原子到粗粒度映射,保留了zwitterionic特征.
- 使用马丁尼3力场进行粗粒度MD模拟,并与全原子模拟进行比较.
- 基于全原子模拟数据,在Martini 3中修复参数化的蛋白质辅助剂相互作用参数.
主要成果:
- 默认的Martini 3参数高估了蛋白质辅助剂接触,表明过度吸引力.
- 重构的Martini 3力场 (Martini 3-exc) 准确地复制了蛋白质与辅助剂的相互作用.
- 新的参数与Fab辅助剂相互作用的全原子模拟结果密切匹配.
结论:
- 开发的Martini 3-exc力场为模拟高度mAb配方提供了经过验证的工具.
- 这一进步使大规模的粗粒度MD模拟能够研究辅助剂的稳定作用.
- 改进的建模有助于开发更稳定,更有效的生物治疗药物.
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