College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
NYU-ECNU Center for Computational Chemistry at NYU, Shanghai, Shanghai 200062, China.
Carbohydr Polym. 2022 Dec 1;297:120050. doi: 10.1016/j.carbpol.2022.120050. Epub 2022 Aug 31.
In computational modelling of cyclodextrin (CD) host-guest binding, often only a single binding mode is considered. However, due to the asymmetric feature of CD, the guest can directionally bind to its primary 6' or secondary 3' face. Correct modelling of the primary-secondary equilibrium clearly poses a challenge. In this work, we present a comprehensive analysis of fixed-charge modelling of β-CD host-guest complexes. Detailed force field evaluations suggest the reliability of the GAFF2 parameter set, but the electrostatics seem difficult to be accurately reproduced even with the RESP charge scheme. Enhanced sampling simulations are performed to accelerate the translational diffusion of the guest, sample the binding/unbinding events and explore the space of possible binding modes. The error size of predicted binding affinities is intermediate and the predicted primary-secondary preferences agree with experiment for only a fraction of host-guest pairs, which should be attributed to the force field inaccuracy (especially electrostatics).
在环糊精（CD）主体-客体结合的计算建模中，通常只考虑一种结合模式。然而，由于 CD 的不对称性，客体可以有方向性地结合到其主要的 6'或次要的 3'面。正确地模拟主-次平衡显然是一个挑战。在这项工作中，我们对 β-CD 主体-客体配合物的固定电荷建模进行了全面分析。详细的力场评估表明 GAFF2 参数集的可靠性，但即使使用 RESP 电荷方案，静电似乎也很难准确再现。增强采样模拟被用来加速客体的平动扩散，采样结合/解吸事件，并探索可能的结合模式的空间。预测结合亲和力的误差大小处于中间水平，预测的主-次偏好与实验结果仅在一部分主体-客体对中一致，这应该归因于力场的不准确性（特别是静电）。
