Protonation in the two-electron/two-proton reduction processes of 2,6-dichlorophenolindophenolate (DCIP) is investigated combining density functional theory (DFT) and molecular dynamics (MD) methods. DCIP (anion), DCIP?– (radical anion), and DCIP2? (dianion) are considered, including the electronic structure analysis from the prospective of quantum theory of atoms and molecules (QTAIM). It is shown that oxygen on the indophenolate moiety and nitrogen are the first and/or the second proton acceptor sites and their energetic order depends on the total charge of the system. MD simulations of differently charged species interacting with the solvent molecules have been performed for methanol, water, and oxonium cation (H3O+). Methanol and water molecules are found to form only hydrogen bonds with the solute irrespective of its charge. The calculated pKa values show that the imino group of DCIPH? is a weaker acid than water. While in the case of DCIP (and DCIP?–) plus oxonium cation, proton transfer from the solvent to the solute was evidenced for both aforementioned acceptor sites. In addition, MD simulations of bulks containing 15 and 43 molecules of water around the DCIP molecule have been performed, revealing the formation of 2–4 hydrogen bonds.
Graphical Abstract 2,6-Dichlorophenolindophenolate interacts with solvent molecules (water, oxonium cation and methanol). Hydrogen transfer and electronic structure are studied by DFT and molecular dynamics methods
Quantum chemical calculations were performed to investigate the stability of the ternary complexes BeH2···XMH3···NH3 (X?=?F, Cl, and Br; M?=?C, Si, and Ge) and the corresponding binary complexes at the atomic level. Our results reveal that the stability of the XMH3···BeH2 complexes is mainly due to both a strong beryllium bond and a weak tetrel–hydride interaction, while the XMH3···NH3 complexes are stabilized by a tetrel bond. The beryllium bond with a halogen atom as the electron donor has many features in common with a beryllium bond with an O or N atom as the electron donor, although they do exhibit some different characteristics. The stability of the XMH3···NH3 complex is dominated by the electrostatic interaction, while the orbital interaction also makes an important contribution. Interestingly, as the identities of the X and M atoms are varied, the strength of the tetrel bond fluctuates in an irregular manner, which can explained by changes in electrostatic potentials and orbital interactions. In the ternary systems, both the beryllium bond and the tetrel bond are enhanced, which is mainly ascribed to increased electrostatic potentials on the corresponding atoms and charge transfer. In particular, when compared to the strengths of the tetrel and beryllium bonds in the binary systems, in the ternary systems the tetrel bond is enhanced to a greater degree than the beryllium bond.
Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors have been demonstrated to possess substantial antitumor activity. VEGFR-2 tyrosine kinase inhibitors are crucial for development of antitumor drugs. Based on the crystal structure of VEGFR-2 tyrosine kinase, a linked-fragment strategy was employed to design novel VEGFR-2 tyrosine kinase inhibitors, and 1000 compounds were generated in this process. Absorption, distribution, metabolism, excretion and toxicity (ADMET) were used to screen the 1000 compounds, and 59 compounds were acceptable. Scaffold hopping was then used for further screening, and only four compounds were obtained in this way. Then, the binding energy of the four molecules to VEGFR-2 tyrosine kinase was calculated using molecular docking, and their values were found to be lower than that of Sorafenib. Finally, molecular dynamics simulations were performed on the complex of the compound with the lowest binding energy with VEGFR-2 tyrosine kinase, and the binding model was analyzed. At the end, four chemical entities with novel structures were obtained, and were suggested for experimental testing in future studies. 相似文献
Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers. To give a comprehensive understanding of molecular mechanism underlying inhibitor response to ALK tyrosine kinase mutations, we established an accurate assessment for the extensive profile of drug against ALK mutations by means of computational approaches. The molecular mechanics-generalized Born surface area (MM-GBSA) method based on molecular dynamics (MD) simulation was carried out to calculate relative binding free energies for receptor-drug systems. In addition, the structure-based virtual screening was utilized to screen effective inhibitors targeting wild-type ALK and the gatekeeper mutation L1196M from 3180 approved drugs. Finally, the mechanism of drug resistance was discussed, several novel potential wild-type and L1196M mutant ALK inhibitors were successfully identified. 相似文献
The σ-hole and π-hole of the protonated 2-halogenated imidazolium cation (XC3H4N2+; X = F, Cl, Br, I) were investigated and analyzed. The monomers of (CH3)3SiY(Y=F, Cl, Br, I), considered as the Lewis base, were combined with the σ-hole and π-hole of XC3H4N2+ to form the σ-hole and π-hole interactions in the bimolecular complexes (CH3)3SiY?·?·?·?XC3H4N2+ and (CH3)3SiY?·?·?·?C3(X)H4N2+(X/Y=F, Cl, Br, I), respectively. For both the σ-hole and π-hole interactions, the equilibrium geometries of complexes show regular changes according to the sequence of heavy sequence of the noncovalent interaction acceptors and donors. The electrostatic energy is the main contribution in the formation of both kinds of interactions, it has linear relations with the VS,max values of σ-hole and the V′S,max values of π-hole. Both the σ-hole and π-hole interactions belong to the closed-shell and noncovalent interactions. The π-hole interactions are stronger than the σ-hole interactions. For the π-hole interactions, the contribution percents of the dispersion energies are somewhat greater than those of the σ-hole interactions, while it is contrary for the polarization energy.
The activation of human epidermal growth factor receptor (hEGFR) involves a large conformational change in its soluble extracellular domains (sECD, residues 1–620), from a tethered to an extended conformation upon binding of ligands, such as EGF. It has been reported that this dynamic process is pH-dependent, that is, hEGFR can be activated by EGF at high pH to form an extended dimer but remains as an inactive monomer at low pH. In this paper, we perform all-atom molecular dynamics (MD) simulations starting from the tethered conformation of sECD:EGF complex, at pH 5.0 and 8.5, respectively. Simulation results indicate that sECD:EGF shows different dynamic properties between the two pHs, and the complex may have a higher tendency of activation at pH 8.5. Twenty residues, including 13 histidines, in sECD:EGF have different protonation states between the two pHs (calculated by the H++ server). The charge distribution at pH 8.5 is more favorable for forming an extended conformation toward the active state of sECD than that at pH 5.0. Our study may shed light on the mechanism of pH dependence of hEGFR activation.
Differing from the weakly antiaromatic B80 buckyball, the medium-sized C1–B28 and D2h–B38, as well as their mono- to tetra-anions, are highly aromatic, as indicated by the negative nucleus-independent chemical shifts (NICSs) at their cage centers. The interior cavities and high aromaticity of the B28 and B38 cages render them very promising hosts to accommodate diverse metal atoms. Accordingly, we carried out systematic density functional theory (DFT) computations on the structures, stabilities and electronic properties of metalloborofullerenes MBn (M?=?Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Sc, Y, La and Ti; n?=?28 and 38). Among them, besides the recently reported M@B38(M?=?Sc, Y and Ti) [Lu et al. (2015) Phys Chem Chem Phys 17:20897–20902], Ti@B28 and M@B38 (M?=?Ca and La) also favor endohedral structures with large binding energies, and are suggested promising targets for experimental applications. Note that Ti@B28 is the first endohedral derivative based on the new B28 fullerene, and La@B38 features the largest metal size inside a B38 cage thus far. These endohedral derivatives, as exemplified by Ca@B38, may exhibit σ and π double aromaticity over the whole cage surface, indicating their considerable stability. In contrast, the other metals prefer to reside at the exterior cage surface, due mainly to the mismatch of their sizes with the boron cages, though the size match is not the only factor to determine their doping form. Furthermore, the infrared absorption spectra and 11B nuclear magnetic resonance spectra of the three new M@Bn complexes were computed to assist future experimental characterization.
The geometries and thermochemistry of Re2(NO)4(CO)n (n?=?4, 3, 2, 1, 0) structures isovalent with the binuclear cobalt carbonyls Co2(CO)n+4 have been examined using density functional theory. Eight low-energy Re2(NO)4(CO)4 structures, all with formal Re–Re single bonds, lie within 6 kcal mol?1 of the global minimum. These eight structures include unbridged structures as well as structures with two bridging NO groups but no structures with bridging CO groups. Similarly, five low-energy Re2(NO)4(CO)3 structures, all with formal Re=Re double bonds, lie within 6 kcal mol?1 of the global minimum. Again these five structures include unbridged structures as well as structures with one or two bridging NO groups but no structures with bridging CO groups. The Re2(NO)4(CO)n (n?=?4, 3) appear to be fluxional systems similar to the well-known Co2(CO)8 for which doubly bridged and unbridged structures have approximately the same energies. The lowest energy Re2(NO)4(CO)2 structures have formal Re=Re double bonds including a structure with a five-electron donor bridging η2-μ-NO group. Isomeric Re2(NO)4(CO)2 structures with formal Re≡Re triple bonds lie approximately ～10 kcal mol?1 above the global minimum. For the more highly unsaturated Re2(NO)4(CO) and Re2(NO)4 systems, the lowest energy structures have formal Re≡Re triple bonds of length ～2.6 Å. Higher energy Re2(NO)4(CO) structures have shorter Re–Re distances of length ～2.5 Å suggesting formal quadruple bonds.
Graphical Abstract The geometries and thermochemistry of Re2(NO)4(CO)n (n?=?4, 3, 2, 1, 0) structures isovalent with the binuclear cobalt carbonyls Co2(CO)n+4 have been examined using density functional theory. A number of energetically closely spaced Re2(NO)4(CO)4 and Re2(NO)4(CO)3 structures are found, including unbridged and NO-bridged structures but no CO-bridged structures. The Re2(NO)4(CO)n (n?=?2, 1, 0) systems provide examples of Re–Re multiple bonds of orders ranging from 2 to 4.
