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集合分子动力学,用于预测DNA间调器的结合能

Anju Choorakottayil Pushkaran¹, Alya A Arabi¹

¹Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University P.O. Box: 15551 Al Ain United Arab Emirates alya.arabi@dal.ca alya.arabi@uaeu.ac.ae.

|March 16, 2026

概括

集成的分子动力学模拟与纠正的MM/PBSA能量准确地预测了DNA-插曲器结合的亲和力. 这种方法为药物发现的实验测量提供了可靠和高效的替代方案.

科学领域:

计算化学计算化学
分子动力学分子动力学
药物发现药物发现药物发现

背景情况:

整体分子动力学 (MD) 模拟提高了蛋白质 - 连接体结合能量的预测.
整体MD对DNA连接体系统的应用较少被探索.
之前的研究集中在特定的DNA插曲器复合物,如多克索鲁比辛和普罗夫拉文.

研究的目的:

扩展整体MD模拟,用于预测各种DNA插曲器复合体的结合能.
评估分子力学/波森-博尔兹曼表面积 (MM/PBSA) 方法的准确性和效率,并进行修正.
为了确定MD复制品的最佳数量,以便可靠地预测结合亲和力.

主要方法:

模拟了 25 个独立的 10 ns MD 复制品,用于 16 个 DNA 间接器复合体.
应用未经纠正和纠正的MM/PBSA方法来计算约束能.
利用引导式分析来评估预测的趋同和不确定性.
用两个额外的单离子级间歇器验证了该方法.

主要成果:

未经校正的MM/PBSA能量显示与实验值的相关性较差 (R2=0.45).
对和变形进行校正的MM/PBSA能量改善了对阴离子间隔器的预测 (R2=0.70,在2kcalmol-1以内).
引导式分析表明,10-20个独立的复制品通常足以进行可靠的预测.

结论:

从整体MD模拟中校正的MM/PBSA能量可靠且有效地预测DNA-间接器结合亲缘关系.
这种计算方法为昂贵或不切实际的实验绑定测量提供了有价值的替代方案.
这些发现支持使用组合MD模拟用于涉及DNA向剂的药物设计和开发.

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