Molecular Biosciences and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Acta Crystallogr D Struct Biol. 2023 Feb 1;79(Pt 2):100-110. doi: 10.1107/S2059798323000025. Epub 2023 Jan 20.
In macromolecular crystallographic structure refinement, ligands present challenges for the generation of geometric restraints due to their large chemical variability, their possible novel nature and their specific interaction with the binding pocket of the protein. Quantum-mechanical approaches are useful for providing accurate ligand geometries, but can be plagued by the number of minima in flexible molecules. In an effort to avoid these issues, the Quantum Mechanical Restraints (QMR) procedure optimizes the ligand geometry in situ, thus accounting for the influence of the macromolecule on the local energy minima of the ligand. The optimized ligand geometry is used to generate target values for geometric restraints during the crystallographic refinement. As demonstrated using a sample of >2330 ligand instances in >1700 protein-ligand models, QMR restraints generally result in lower deviations from the target stereochemistry compared with conventionally generated restraints. In particular, the QMR approach provides accurate torsion restraints for ligands and other entities.
在大分子晶体学结构精修中，由于配体的化学变异性大、可能具有新颖性以及与蛋白质结合口袋的特异性相互作用，为其生成几何约束条件颇具挑战。量子力学方法有助于提供准确的配体几何形状，但可能会受到柔性分子中局部最小值数量的困扰。为了避免这些问题，量子力学约束（QMR）程序可以在原位优化配体的几何形状，从而考虑大分子对配体局部能量最小值的影响。优化后的配体几何形状用于在晶体学精修过程中生成几何约束的目标值。通过对超过 2330 个配体实例和超过 1700 个蛋白-配体模型的样本进行验证，与传统生成的约束条件相比，QMR 约束条件通常可以使偏离目标立体化学的程度更小。特别是，QMR 方法可以为配体和其他实体提供准确的扭转约束条件。
