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首页> 外文期刊>Acta crystallographica. Section D, Structural biology >Exploring ligand dynamics in protein crystal structures with ensemble refinement
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Exploring ligand dynamics in protein crystal structures with ensemble refinement

机译：探索配体动力学在蛋白质晶体结构整体优化

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摘要

Understanding the dynamics of ligands bound to proteins is an important task in medicinal chemistry and drug design. However, the dominant technique for determining protein-ligand structures, X-ray crystallography, does not fully account for dynamics and cannot accurately describe the movements of ligands in protein binding sites. In this article, an alternative method, ensemble refinement, is used on six protein-ligand complexes with the aim of understanding the conformational diversity of ligands in protein crystal structures. The results show that ensemble refinement sometimes indicates that the flexibility of parts of the ligand and some protein side chains is larger than that which can be described by a single conformation and atomic displacement parameters. However, since the electron-density maps are comparable and Rfree values are slightly increased, the original crystal structure is still a better model from a statistical point of view. On the other hand, it is shown that molecular-dynamics simulations and automatic generation of alternative conformations in crystallographic refinement confirm that the flexibility of these groups is larger than is observed in standard refinement. Moreover, the flexible groups in ensemble refinement coincide with groups that give high atomic displacement parameters or non-unity occupancy if optimized in standard refinement. Therefore, the conformational diversity indicated by ensemble refinement seems to be qualitatively correct, indicating that ensemble refinement can be an important complement to standard crystallographic refinement as a tool to discover which parts of crystal structures may show extensive flexibility and therefore are poorly described by a single conformation. However, the diversity of the ensembles is often exaggerated (probably partly owing to the rather poor force field employed) and the ensembles should not be trusted in detail.
机译：了解配体的动态绑定在药用蛋白质是一个重要的任务化学和药物设计。技术决定protein-ligand结构,x射线晶体学,并不完全占动态和不准确描述的运动配体的蛋白质结合位点。整体改进,方法是使用6protein-ligand复合物的目的理解构象的多样性配体的蛋白质晶体结构。结果表明,有时合奏细化显示部分的灵活性配体和蛋白质侧链比较大比可由一个描述构象和原子位移参数。然而,由于电子密度图可比性和Rfree值增加,原有的晶体结构从统计的角度还是一个更好的模型视图。分子动力学模拟和自动代替代构象晶体细化确认这些组织的灵活性比在标准的细化。灵活的组织整体优化一致组给予高原子位移如果优化参数或复本入住率标准的细化。构象多样性所示细化似乎定性正确,表明整体优化可能是一个重要的补充标准晶体精致的工具发现的哪些部分晶体结构显示广泛的灵活性因此不被描述由一个构象。乐团经常被夸大(可能是部分由于使用的,而可怜的力场)乐团不应该相信细节。

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