Inclusion of multiple fragment types in the site identification by ligand competitive saturation (SILCS) approach.
Inclusion of multiple fragment types in the site identification by ligand competitive saturation (SILCS) approach.
复制标题
通过配体竞争饱和（SILCS）方法在现场识别中包含多种片段类型。
DOI：
10.1021/ci4005628
复制
发表时间：
2013-12-23
影响因子：
5.6
通讯作者：
MacKerell AD Jr
中科院分区：
文献类型：
--
作者：
Raman EP;Yu W;Lakkaraju SK;MacKerell AD Jr
通过配体竞争饱和的位点鉴定（SILCS）方法通过在代表不同化学官能团的小分子的水溶液中对靶进行分子动力学（MD）模拟来鉴定靶大分子表面上的小分子片段的位置和近似亲和力。在这项研究中，我们引入了一组小分子来映射潜在的相互作用，由中性氢键供体和受体，以及带电的供体和受体片段，除了非极性片段。亲和模式以离散化概率的形式获得，或者等价地，以自由能图的形式获得，称为FragMaps，其可以用目标表面可视化。我们进行了SILCS模拟四种蛋白质的结构和热力学数据是可用于多个，不同的配体。良好的重叠之间的高亲和力区域的FragMaps和具有类似的化学功能的配体官能团的晶体位置，从而证明了从模拟获得的定性信息的有效性。为了测试FragMaps在提供定量预测方面的能力，我们计算了先前引入的配体网格自由能（LGFE）度量，并观察其与实验测量的结合亲和力的对应关系。LGFE计算不同的构象合奏和改进的预测显示，随着配体构象采样。包围圈生成包括直接使用GFE FragMaps作为能量函数的Monte Carlo采样方法。结果表明，一些，但不是所有的实验趋势的预测，并保证改进的评分方法。此外，基于原子的自由能贡献的LGFE分数和使用SILCS中的多个配体，以确定可置换的水分子在配体设计的潜在效用进行了讨论。
The Site Identification by Ligand Competitive Saturation (SILCS) method identifies the location and approximate affinities of small molecular fragments on a target macromolecular surface by performing Molecular Dynamics (MD) simulations of the target in an aqueous solution of small molecules representative of different chemical functional groups. In this study, we introduce a set of small molecules to map potential interactions made by neutral hydrogen bond donors and acceptors, and charged donor and acceptor fragments in addition to nonpolar fragments. The affinity pattern is obtained in the form of discretized probability or, equivalently, free energy maps, called FragMaps, which can be visualized with the target surface. We performed SILCS simulations for four proteins for which structural and thermodynamic data is available for multiple, diverse ligands. Good overlap is shown between high affinity regions identified by the FragMaps and the crystallographic positions of ligand functional groups with similar chemical functionality, thus demonstrating the validity of the qualitative information obtained from the simulations. To test the ability of FragMaps in providing quantitative predictions, we calculate the previously introduced Ligand Grid Free Energy (LGFE) metric and observe its correspondence with experimentally measured binding affinity. LGFE is computed for different conformational ensembles and improvement in prediction is shown with increasing ligand conformational sampling. Ensemble generation includes a Monte Carlo sampling approach that uses the GFE FragMaps directly as the energy function. The results show some, but not all experimental trends are predicted, and warrant improvements in the scoring methodology. In addition, the potential utility of atom-based free energy contributions to the LGFE scores and the use of multiple ligands in SILCS to identify displaceable water molecules during ligand design are discussed.
登录
查看更多内容
影响因子：
15
作者：
Abel, Robert;Young, Tom;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
影响因子：
5.5
作者：
Bakan, Ahmet;Nevins, Neysa;Lakdawala, Ami S.;Bahar, Ivet
通讯作者：
Bahar, Ivet
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
2.9
作者：
Adler, M;Davey, DD;Whitlow, M
通讯作者：
Whitlow, M