非物理结构崩在量子力学计算中使用连续溶解.
Andreas H Göller1, Dieudonné T Tshitenge2
1Structrual Biology and Computational Design, Bayer AG Pharmaceuticals, Wuppertal, Germany.
概括
可极化连续模型 (CPCM,SMD) 无法准确预测类似药物的分子构造. 显式溶解模拟和NMR实验揭示了这些模型的非物理结果,突出了改进溶解方法的需要.
科学领域:
- 计算化学是一种计算化学.
- 分子建模分子建模
- 药物发现 药物发现
背景情况:
- 像CPCM和SMD这样的极化连续模型 (PCMs) 广泛用于溶解.
- 准确预测分子构造对于药物设计至关重要.
研究的目的:
- 评估CPCM和SMD模型在描述药物样分子的结构能量方面的表现.
- 为了比较计算预测与实验数据 (NMR) 和明确的溶解模拟.
主要方法:
- 基于量子力学 (QM) 的CREST工作流和OPLS4力场模拟 (MCMM) 用于符合组合生成.
- 使用r2SCAN-3c和r2SCAN-d3 (BJ) /aug-cc-pVTZ进行了优化.
- 使用了通用化-Born/表面积 (GB/SA) 连续溶剂模型.
- 进行了1D/2D NMR实验 (NOESY) 和显式溶解分子动力学模拟.
主要成果:
- QM 和 OPLS4/CPCM 方法主要产生了崩的 π 堆叠形状.
- 在OPLS4/GB/SA模拟中,结果是延伸的形状.
- 核磁共振实验和显式溶解模拟表明最小的 (<5%) 崩的形状.
结论:
- 标准的PCM实现不能准确地表示溶剂相互作用 (特定,定向) 并忽视贡献.
- 连续性溶解模型导致研究分子的非物理形态组合.
- 需要更复杂的溶解模型来进行准确的构造分析.
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