PDB ligand conformational energies calculated quantum-mechanically.
PDB ligand conformational energies calculated quantum-mechanically.
复制标题
DOI：
10.1021/ci200595n
复制
发表时间：
2012-03-26
影响因子：
5.6
通讯作者：
Nicklaus MC
中科院分区：
文献类型：
--
作者：
Sitzmann M;Weidlich IE;Filippov IV;Liao C;Peach ML;Ihlenfeldt WD;Karki RG;Borodina YV;Cachau RE;Nicklaus MC
我们在这里提出了一个大大更新的版本的早期研究蛋白质数据库（PDB）中的蛋白质-配体复合物的构象能[尼克劳斯等人。1995，3，411 - 428]，目的是改进所有可能的方面，例如配体实例的数量和选择、进行的能量计算和进行的附加分析。从PDB中所有小分子实例的实验3D坐标的2008版Ligand Expo数据库中存储的约357，000个配体实例开始，我们通过各种过滤步骤创建了配体实例的“高质量”子集，包括应用晶体学质量标准和结构明确性。提交640个高斯03作业产生了一组约415个成功结束的运行。我们使用B3 LYP/6- 31 G（d）基组在DFT理论水平上逐步优化内部自由度，并在每一轮（部分）优化后在B3 LYP/6-311++G（3df，2 p）上进行单点能量计算，以分离由于键长拉伸、键角变化和扭转变化引起的能量变化。即使对于所有可能的构象能量中最“保守”的选择--除了扭转之外的所有内部自由度都被优化的构象与完全优化的构象之间的能量差--也发现了显著的能量值。0至1.25千卡/摩尔的范围是相当均匀的，并且与晶体学分辨率无关。只有在1.3 μ m以上的分辨率下才能看到少量更高能量的“离群值”。能量显示出与分子大小和灵活性的一些相关性，但与晶体学质量指标（如Cruickshank衍射组分精度指数（DPI）和Rfree-R）或配体实例特定指标（如占用加权B因子（OWAB），实空间R因子（RSR）和实空间相关系数（RSCC））无关。我们用溶剂模型IEFPCM重复了这些计算，得到的能量差通常略低于相应的真空结果，但没有产生质的不同。使用MMFF 94 s力场在分子力学水平上围绕晶体构象进行扭转采样通常会导致能量增加。
We present here a greatly updated version of an earlier study on the conformational energies of protein−ligand complexes in the Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med. Chem. 1995, 3, 411−428], with the goal of improving on all possible aspects such as number and selection of ligand instances, energy calculations performed, and additional analyses conducted. Starting from about 357,000 ligand instances deposited in the 2008 version of the Ligand Expo database of the experimental 3D coordinates of all small-molecule instances in the PDB, we created a “high-quality” subset of ligand instances by various filtering steps including application of crystallographic quality criteria and structural unambiguousness. Submission of 640 Gaussian 03 jobs yielded a set of about 415 successfully concluded runs. We used a stepwise optimization of internal degrees of freedom at the DFT level of theory with the B3LYP/6–31G(d) basis set and a single-point energy calculation at B3LYP/6–311++G(3df,2p) after each round of (partial) optimization to separate energy changes due to bond length stretches vs bond angle changes vs torsion changes. Even for the most “conservative” choice of all the possible conformational energies— the energy difference between the conformation in which all internal degrees of freedom except torsions have been optimized and the fully optimized conformer—significant energy values were found. The range of 0 to ∼25 kcal/mol was populated quite evenly and independently of the crystallographic resolution. A smaller number of “outliers” of yet higher energies were seen only at resolutions above 1.3 Å. The energies showed some correlation with molecular size and flexibility but not with crystallographic quality metrics such as the Cruickshank diffraction-component precision index (DPI) and Rfree-R, or with the ligand instance-specific metrics such as occupancy-weighted B-factor (OWAB), real-space R factor (RSR), and real-space correlation coefficient (RSCC). We repeated these calculations with the solvent model IEFPCM, which yielded energy differences that were generally somewhat lower than the corresponding vacuum results but did not produce a qualitatively different picture. Torsional sampling around the crystal conformation at the molecular mechanics level using the MMFF94s force field typically led to an increase in energy.
登录
查看更多内容
影响因子：
56.9
作者：
Burling, FT;Weis, WI;Brunger, AT
通讯作者：
Brunger, AT
影响因子：
3.5
作者：
Bostrom, J;Norrby, PO;Liljefors, T
通讯作者：
Liljefors, T
DOI：
10.1107/s0907444903026209
发表时间：
2004-02-01
影响因子：
2.2
作者：
Afonine, PV;Lunin, VY;Urzhumtsev, A
通讯作者：
Urzhumtsev, A
DOI：
10.1107/s0907444902003931
发表时间：
2002-05-01
影响因子：
2.2
作者：
Blow, DM
通讯作者：
Blow, DM
DOI：
10.1021/ci980404z
发表时间：
1998-11-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
Demeter, DA;Weintraub, HJR;Knittel, JJ
通讯作者：
Knittel, JJ