Exploring protein flexibility: incorporating structural ensembles from crystal structures and simulation into virtual screening protocols.
Exploring protein flexibility: incorporating structural ensembles from crystal structures and simulation into virtual screening protocols.
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DOI：
10.1021/jp3003992
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发表时间：
2012-06-14
期刊：
影响因子：
--
通讯作者：
Hagler AT
中科院分区：
文献类型：
--
作者：
Osguthorpe DJ;Sherman W;Hagler AT
蛋白质对包括共价修饰在内的各种扰动以及与配体和其他蛋白质的相互作用的适应能力在生物过程中起着关键作用。在这里，我们探索分子动力学(MD)、副本交换分子动力学(REMD)和晶体-配体复合体结构库的能力，以采样蛋白质构象图景，特别是可访问的配体结合位置几何。通过配体结合位点形状的多样性来衡量采样的构象空间的程度。由于我们这里的重点是这种可塑性对通过虚拟筛选识别活性化合物的能力的影响，我们使用这些技术生成的结构为进一步的对接研究生成一个小集合，使用结合位点形状层次聚类来确定每个集合的四个结构，然后评估它们在对接中优化浓缩和多样性的能力。我们在三种不同的受体上测试了这些协议：雄激素受体(AR)、HIV蛋白水解酶和CDK2。我们发现，与MD相比，REMD略微增强了结构采样，并且反映在晶体结构中的是配体结合引起的扭曲。然而，模拟方法的改进采样并不能直接转化为改进的对接性能。系综方法确实改善了丰富性和多样性，从晶体结构得出的系综表现略好于从模拟得出的系综。
The capacity of proteins to adapt their structure in response to various perturbations including covalent modifications, and interactions with ligands and other proteins plays a key role in biological processes. Here, we explore the ability of molecular dynamics (MD), replica exchange molecular dynamics (REMD) and a library of structures of crystal-ligand complexes, to sample the protein conformational landscape and especially the accessible ligand binding site geometry. The extent of conformational space sampled is measured by the diversity of the shapes of the ligand binding sites. Since our focus here is the effect of this plasticity on the ability to identify active compounds through virtual screening, we use the structures generated by these techniques to generate a small ensemble for further docking studies, using binding site shape hierarchical clustering to determine four structures for each ensemble These are then assessed for their capacity to optimize enrichment and diversity in docking. We test these protocols on three different receptors: androgen receptor (AR), HIV protease, and CDK2. We show that REMD enhances structural sampling slightly as compared both to MD, and the distortions induced by ligand binding as reflected in the crystal structures. The improved sampling of the simulation methods doesn’t translate directly into improved docking performance however. The ensemble approach did improve enrichment and diversity, and, the ensemble derived from the crystal structures performed somewhat better than those derived from the simulations.
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影响因子：
5.6
作者：
Halgren, Thomas A.
通讯作者：
Halgren, Thomas A.
DOI：
10.1073/pnas.2335541100
发表时间：
2003-11-25
影响因子：
11.1
作者：
García, AE;Onuchic, JN
通讯作者：
Onuchic, JN
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
影响因子：
1.7
作者：
Martyna, GJ;Tuckerman, ME;Klein, ML
通讯作者：
Klein, ML
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL