Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94143 United States.
BioPharmics LLC, Santa Rosa, California 95404 United States.
J Med Chem. 2020 Sep 24;63(18):10509-10528. doi: 10.1021/acs.jmedchem.0c01373. Epub 2020 Sep 14.
We report a new method for X-ray density ligand fitting and refinement that is suitable for a wide variety of small-molecule ligands, including macrocycles. The approach (called "xGen") augments a force field energy calculation with an electron density fitting restraint that yields an energy reward during the restrained conformational search. The resulting conformer pools balance goodness-of-fit with ligand strain. Real-space refinement from pre-existing ligand coordinates of 150 macrocycles resulted in occupancy-weighted conformational ensembles that exhibited low strain energy. The xGen ensembles improved upon electron density fit compared with the PDB reference coordinates without making use of atom-specific B-factors. Similarly, on nonmacrocycles, fitting produced occupancy-weighted ensembles of many conformers that were generally better-quality density fits than the deposited primary/alternate conformational pairs. The results suggest ubiquitous low-energy ligand conformational ensembles in X-ray diffraction data and provide an alternative to using B-factors as model parameters.
我们报告了一种新的 X 射线密度配体拟合和精修方法，适用于各种小分子配体，包括大环配体。该方法（称为“xGen”）在力场能量计算中增加了电子密度拟合约束，在约束构象搜索过程中产生能量奖励。由此产生的构象池在配体应变与拟合度之间取得平衡。从 150 个大环的现有配体坐标进行实空间精修，得到了占据权重的构象系综，表现出低应变能。与不使用原子特定 B 因子的 PDB 参考坐标相比，xGen 系综在电子密度拟合方面表现更好。类似地，对于非大环配体，拟合产生了许多构象的占据权重的系综，这些系综的密度拟合通常比已存储的主要/替代构象对质量更高。结果表明，X 射线衍射数据中存在普遍的低能配体构象系综，并提供了一种替代使用 B 因子作为模型参数的方法。
