Charge density distribution and the electrostatic moments of CTPB in the active site of p300 enzyme: A DFT and charge density study

• Published in: Journal of theoretical biology 2013-10, Vol.335, p.119-129
• Main Authors: Devipriya, B., Kumaradhas, P.
• Format: Article
• Language: English
• Subjects: amino acids; Benzamides - chemistry; Catalytic Domain; E1A-Associated p300 Protein - chemistry; Electrostatic potential; energy; gases; Humans; hydrogen bonding; Intermolecular interactions; Molecular docking; Molecular Docking Simulation; Molecular Dynamics Simulation; Quantum chemical calculations; Static Electricity; Tryptophan - chemistry; Tyrosine - chemistry
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2013.06.001

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. A molecular docking and charge density analysis have been carried out to understand the conformational change, charge distribution and electrostatic properties of CTPB in the active site of p300. Due to the intermolecular interaction between CTPB and amino acids, the conformation of CTPB has been changed (particularly the pentadecyl chain). The density ρbcp(r) of the polar bonds are found increases when it present in the active site. [Display omitted] •The amide bonds are responsible for HAT activation of p300 in CTPB.•The pentadecyl chain of CTPB in the active site is twisted due to intermolecular interactions.•In the active site, an extension of positive contour is found in