Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics, Periyar University, Salem 636011, India.
J Theor Biol. 2013 Oct 21;335:119-29. doi: 10.1016/j.jtbi.2013.06.001. Epub 2013 Jun 13.
A molecular docking and charge density analysis have been carried out to understand the conformational change, charge distribution and electrostatic properties of N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide (CTPB) in the active site of p300. The nearest neighbors, shortest intermolecular contacts between CTPB-p300 and the lowest binding energy of CTPB have been analyzed from the docking analysis. Further, a charge density analysis has been carried out for the molecule in gas phase and for the corresponding molecule lifted from the active site of p300. Due to the intermolecular interaction between CTPB and the amino acids of active site, the conformation of the CTPB has been significantly altered (particularly the pentadecyl chain). CTPB forms strong interaction with the amino acid residues Tyr1397 and Trp1436 at the distance 2.12 and 2.72Å, respectively. However, the long pentadecyl alkyl chain of CTPB produces a barrier and reducing the chance of forming hydrogen bonding with p300. The electron density ρbcp(r) of the polar bonds (C-O, C-N, C-F and C-Cl) of CTPB are increased when it present in the active site. The dipole moment of CTPB in the active site is significantly less (5.73D) when compared with the gas phase (8.16D) form. In the gas phase structure, a large region of negative electrostatic potential (ESP) is found at the vicinity of O(2) and CF3 group, which is less around the O(1) atom. Whereas, in the active site, the negative ESP around the CF3 group is decreased and increased at the O(1) and O(2)-atoms. The ESP modifications of CTPB in the active site are mainly attributed to the effect of intermolecular interaction. The gas phase and active site study insights the molecular flexibility and the electrostatic properties of CTPB in the active site.
进行了分子对接和电荷密度分析，以了解 N-(4-氯-3-三氟甲基-苯基)-2-乙氧基-6-十五烷基苯甲酰胺（CTPB）在 p300 活性部位的构象变化、电荷分布和静电性质。从对接分析中分析了 CTPB-p300 的最近邻和最短分子间接触，以及 CTPB 的最低结合能。此外，还对气相中和从 p300 活性部位提取的相应分子进行了电荷密度分析。由于 CTPB 与活性部位氨基酸之间的分子间相互作用，CTPB 的构象发生了显著变化（特别是十五烷基链）。CTPB 与活性部位的氨基酸残基 Tyr1397 和 Trp1436 分别以 2.12 和 2.72Å 的距离形成强相互作用。然而，CTPB 的长十五烷基链会产生阻碍，减少与 p300 形成氢键的机会。当 CTPB 存在于活性部位时，其极性键（C-O、C-N、C-F 和 C-Cl）的电子密度 ρbcp(r)增加。与气相（8.16D）相比，CTPB 在活性部位的偶极矩显著减小（5.73D）。在气相结构中，在 O(2)和 CF3 基团附近发现了一个大的负静电势（ESP）区域，而在 O(1)原子附近则较少。然而，在活性部位，CF3 基团周围的负 ESP 减少，而 O(1)和 O(2)-原子周围的负 ESP 增加。CTPB 在活性部位的 ESP 修饰主要归因于分子间相互作用的影响。气相和活性部位研究深入了解了 CTPB 在活性部位的分子柔性和静电性质。
