Conformational Analysis of Free and Bound Retinoic Acid
Conformational Analysis of Free and Bound Retinoic Acid
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DOI：
10.1021/ct200813q
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发表时间：
2012-04-01
影响因子：
5.5
通讯作者：
Merz, Kenneth M., Jr.
中科院分区：
文献类型：
--
作者：
Fu, Zheng;Li, Xue;Merz, Kenneth M., Jr.
用经典和量子力学方法研究了全反式和9-顺式维甲酸（RA）的构象。通过真空HF/6 - 31 G * 几何优化，鉴定了66种全反式RA（ATRA）和48种9-顺式RA能量最小构象。使用M06、M06 - 2x和MP2方法结合6 - 311 + G（d，p）、aug-cc-pVDZ和aug-cc-pVTZ基组以及使用后两个基组的完整基组MP2外推来估计它们的相对构象能。单点能量计算与M06 - 2x密度泛函被发现产生类似的结果MP2/CBS的低能量视黄酸构象。不出所料，视黄酸的构象倾向由与多烯尾部相关的扭转角的取向和排列决定。我们还使用了以前报道的QM/MM X-射线精修结果的四个ATRA-蛋白质晶体结构加上一个新的精制9-顺式RA复合物（PDB ID：1XDK），以调查结合维甲酸的构象偏好。在rerefined RA构象，共轭双键几乎是共面的，这是一致的全球最低确定的欧米茄/QM方法，而不是相应的晶体学确定的构象中给出的PDB。因此，一个91.3%的平均减少的局部应变能在气相中，以及92.1%的PCM溶剂中，观察到使用QM/MM精制结构与PDB沉积RA构象。因此，这些结果表明，我们的QM/MM X射线细化方法可以显着提高X射线晶体结构的质量，通过传统的细化协议，从而提供可靠的药物靶结构信息，用于基于结构的药物发现应用。
The conformational profiles of unbound all-trans and 9-cis retinoic acid (RA) have been determined using classical and quantum mechanical calculations. Sixty-six all-trans-RA (ATRA) and 48 9-cis-RA energy minimum conformers were identified via HF/6-31G* geometry optimizations in vacua. Their relative conformational energies were estimated utilizing the M06, M06-2x, and MP2 methods combined with the 6-311+G(d,p), aug-cc-pVDZ, and aug-cc-pVTZ basis sets, as well as complete basis set MP2 extrapolations using the latter two basis sets. Single-point energy calculations performed with the M06-2x density functional were found to yield similar results to MP2/CBS for the low-energy retinoic acid conformations. Not unexpectedly, the conformational propensities of retinoic acid were governed by the orientation and arrangement of the torsion angles associated with the polyene tail. We also used previously reported QM/MM X-ray refinement results on four ATRA-protein crystal structures plus one newly refined 9-cis-RA complex (PDB ID: 1XDK) in order to investigate the conformational preferences of bound retinoic acid. In the rerefined RA conformers, the conjugated double bonds are nearly coplanar, which is consistent with the global minimum identified by the Omega/QM method rather than the corresponding crystallographically determined conformations given in the PDB. Consequently, a 91.3% average reduction of the local strain energy in the gas phase, as well as 92.1% in PCM solvent, was observed using the QM/MM refined structures versus the PDB deposited RA conformations. These results thus demonstrate that our QM/MM X-ray refinement approach can significantly enhance the quality of X-ray crystal structures refined by conventional refinement protocols, thereby providing reliable drug-target structural information for use in structure-based drug discovery applications.