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首页> 外文期刊>RSC Advances >Calculations of the absolute binding free energies for Ralstonia solanacearum lectins bound with methyl-α-L-fucoside at molecular mechanical and quantum mechanical/molecular mechanical levels
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Calculations of the absolute binding free energies for Ralstonia solanacearum lectins bound with methyl-α-L-fucoside at molecular mechanical and quantum mechanical/molecular mechanical levels

机译：分子力学和量子力学/分子力学水平上与甲基-α-L-岩藻糖苷结合的青枯雷尔氏菌植物凝集素的绝对结合自由能的计算

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A method that can reliably predict protein–ligand binding free energies is essential for rational drug design. Much effort has been devoted to this field, but it remains challenging especially for flexible ligands. In this work, both a molecular mechanical (MM) method and a hybrid quantum mechanical/molecular mechanical (QM/MM) method have been applied in the study of the binding affinities of methyl-α-L-fucoside to Ralstonia solanacearum lectins. The free energy at the MM level was calculated using the double-decoupling method (DDM) and the free energy change at each step was calculated via a series of intermediate states using the Bennett acceptance ratio (BAR). The binding free energy agrees well with the experimental measurement, no matter whether the general AMBER force field or GLYCAM06j was applied to the ligand. Nonetheless, slow convergence for some intermediate states has been observed, which requires substantially longer simulations than were used in many other studies. The QM/MM free energy was calculated by thermodynamic perturbation (TP) from the MM states. This strategy has been shown to yield minimal variance for the calculated free energy without direct sampling at the QM/MM level in a previous study. However, after this MM-to-QM/MM correction, the agreement with the experimental value decreased. This study serves as an implication of the demand for substantially longer simulations for the alchemical process than those that were used in many other studies and for further improvement of QM/MM methods, especially the description of interactions between the QM and MM regions.
机译：能够可靠地预测蛋白质与配体结合的自由能的方法对于合理的药物设计至关重要。在该领域已经付出了很多努力，但是尤其对于柔性配体而言，它仍然具有挑战性。在这项工作中，分子力学（MM）方法和混合量子力学/分子力学（QM / MM）方法已被用于研究甲基-α- L -的结合亲和力岩藻糖苷对 Ralstonia solanacearum 凝集素的作用。使用双解耦方法（DDM）计算MM级的自由能，并使用Bennett接受率（BAR）通过一系列中间状态 计算每个步骤的自由能变化。无论是将普通的AMBER力场还是将GLYCAM06j施加到配体上，结合自由能都与实验测量结果非常吻合。然而，已经观察到某些中间状态的缓慢收敛，这需要比许多其他研究中所使用的更长的模拟时间。通过热力学扰动（TP）从MM状态计算QM / MM自由能。在先前的研究中，这种策略已显示出无需计算直接在QM / MM级别上获得的自由能的最小方差。但是，经过MM到QM / MM的校正后，与实验值的一致性降低了。这项研究表明，对于炼金工艺的仿真要比在许多其他研究中使用的仿真更长，并且需要进一步改进QM / MM方法，尤其是描述QM和MM区域之间相互作用的需求。

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