提高含有金属的配体受体复合物的FMO结合亲和力预测的准确性
R Paciotti1, A Marrone2, C Coletti2
1Department of Pharmacy, Università "G. D'Annunzio" Di Chieti-Pescara, Chieti, Italy. r.paciotti@unich.it.
Journal of computer-aided molecular design
|September 24, 2023
概括
这项研究完善了碎片分子轨道 (FMO) 方法,以准确计算金属基联体与DNA G-四重复合物的结合亲和力. 改进的协议使用选的静电电位,为这些复杂的生物系统产生更可靠的相互作用能量.
科学领域:
- 计算化学的计算化学
- 分子建模分子建模
- 生物化学 生物化学
背景情况:
- 涉及金属原子的配体-受体相互作用,例如Au(I) - 双烯复合体与DNA G-四重复合体,受到极化和电荷转移的显著影响.
- 之前的初始碎片分子轨道 (FMO2) 计算在RI-MP2/6-31G*级别使用PCM溶解高估了电荷转移能量,导致与实验数据难以比较的结合能量.
- 准确预测结合亲和力对于理解和设计以金属为基础的药物来向DNA G-四重复合体至关重要.
研究的目的:
- 提高FMO方法的准确性,用于预测金属基联结体与DNAG-四重复合体 (Gq) 的结合亲和力.
- 评估包括电子相关性在内的计算参数,FMO方法 (FMO2与FMO3),基础集大小和静电电位 (ESP) 对绑定能量计算的影响.
- 提出一种改进的计算协议,用于使用FMO方法研究含有金属的生物系统.
主要方法:
- 计算特征的系统评估:Hartree-Fock (HF) 和RI-MP2用于电子相关性,FMO2和FMO3方法,基数变化 (带有偏振功能的双ζ和三ζ),以及不同的静电电位 (ESP) 处理.
- 在所有计算中应用部分选方法来模拟溶剂选效应.
- 计算绑定能量 (ΔEFMO) 和配体-受体对相互作用能量 (EINT) 的Au(I) - biscarbene衍生物与DNAG-四重复.
主要成果:
- 使用ESP计算所有原子的选点电荷 (ESP-SPTC) 极大地提高了 ΔEFMO 和 EINT 的准确性.
- ESP-SPTC消除了对电荷转移能量的过高估计,导致能量值与典型的实验结合能相比较.
- 相互作用能量 (EINT) 值更准确地描述了与 ΔEFMO 相比,金属基结合剂与 DNA Gq 的结合效率.
结论:
- 部分选溶剂方法和ESP-SPTC的结合为使用FMO方法研究含金属系统提供了更准确的计算方法.
- 对于含有金属的生物系统的FMO计算,建议使用这种精细的计算协议,特别是当默认ESP处理产生可疑结果时.
- 该研究强调了仔细选择计算参数的重要性,以实现对与DNA相互作用的金属药物可靠的结合亲和力预测.
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