Katzberger Paul, Hauswirth Lea M, Kuhn Antonia S, Landrum Gregory A, Riniker Sereina
Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, Zürich 8093, Switzerland.
J Am Chem Soc. 2025 Apr 23;147(16):13264-13275. doi: 10.1021/jacs.4c17622. Epub 2025 Apr 10.
Understanding and manipulating the conformational behavior of a molecule in different solvent environments is of great interest in the fields of drug discovery and organic synthesis. Molecular dynamics (MD) simulations with solvent molecules explicitly present are the gold standard to compute such conformational ensembles (within the accuracy of the underlying force field), complementing experimental findings and supporting their interpretation. However, conventional methods often face challenges related to computational cost (explicit solvent) or accuracy (implicit solvent). Here, we showcase how our graph neural network (GNN)-based implicit solvent (GNNIS) approach can be used to rapidly compute small molecule conformational ensembles in 39 common organic solvents reproducing explicit-solvent simulations with high accuracy. We validate this approach using nuclear magnetic resonance (NMR) measurements, thus identifying the conformers contributing most to the experimental observable. The method allows the time required to accurately predict conformational ensembles to be reduced from days to minutes while achieving results within one of the experimental values.
在药物发现和有机合成领域,了解并操控分子在不同溶剂环境中的构象行为具有重大意义。明确包含溶剂分子的分子动力学(MD)模拟是计算此类构象集合(在基础力场的精度范围内)的金标准,它能补充实验结果并支持对其的解释。然而,传统方法常常面临与计算成本(显式溶剂)或精度(隐式溶剂)相关的挑战。在此,我们展示了基于图神经网络(GNN)的隐式溶剂(GNNIS)方法如何能够快速计算39种常见有机溶剂中的小分子构象集合,高精度地重现显式溶剂模拟。我们使用核磁共振(NMR)测量来验证这种方法,从而确定对实验观测值贡献最大的构象。该方法能够将准确预测构象集合所需的时间从数天缩短至数分钟,同时获得与实验值相差在一个数量级内的结果。
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