Journal of Theoretical and Computational Chemistry

Protease-activated receptor 4 (PAR4) is a promising target for antiplatelet therapy. In this study, homology modeling and molecular docking methods were used to investigate the binding modes of PAR4 agonists and antagonists. The outcomes show that agonists have good docking scores, and they also form more hydrogen bonds with PAR4 than antagonists. To reveal the different conformational changes caused by agonist and antagonist, molecular dynamic simulations were carried out on three selected PAR4 systems. Simulation results show that PAR4 activation involves breaking interactions of 3–7 lock switch (Try157 and Tyr322) and ionic lock switch (Arg188 and Asp173), and formation of transmission switch among Tyr161, Asn300 and Phe296. In addition, principal component analysis (PCA) indicates that the major change for agonist bound system takes place in the intracellular region while that for antagonist bound system is in the extracellular region. The binding free energy of BMS-986120 is much lower than AYPGKF, suggesting high affinity of antagonist. Moreover, the electronegative aspartic residues Asp230 and Asp235 at ECL2 are important for PAR4 binding to agonist. Clarifying the PAR4 structural characteristics may be helpful to understand the activation mechanism, giving insights into the molecular design and discovery of novel potential PAR4 antagonists in the future.

The FTIR spectrum of acetanilide (ACN) is recorded and analyzed. The optimized molecular structures, harmonic vibrational wavenumbers and corresponding vibrational assignments of the ACN are computationally examined by using the B3LYP density functional theory method together with the standard 6-311$++$G($d$,$p$) basis set. From the calculations, the ACN is predicted to exist predominantly in trans configuration with the relative energy, rotational barrier, and population of 2.8kcal/mol, 14.8kcal/mol, and 99.5%, respectively. The optimized structure shows that the amide group (CO–NH) of trans-ACN adopts a planar peptide-like conformation. The effect of the incorporation of dispersion correction to the B3LYP on the calculated equilibrium structure and vibrational spectra of ACN is investigated. The highest occupied and the lowest unoccupied molecular orbitals, IR intensities and molecular electrostatic potential results are reported. In addition, reliable vibrational assignments have been made on the basis of Potential Energy Distribution (PED) using VEDA4 program. Simulated IR spectrum are compared with the experimental FTIR and FT-Raman spectra. Energy decomposition analysis (EDA) revealed that Pauli repulsion is responsible for the increased stability of the trans over the cis isomer.

The interactions of carbon dioxide with the anorthite (001) surface and the influence of H₂O on the adsorption were studied using the density functional theory (DFT) calculations on periodic slab systems. Of the various available sites, CO₂ binding was calculated to be strongly adsorbed to calcium atoms and oxygen atoms on the tetrahedral Al and Si sites, with quite high adsorption energy values ($>20$kcal/mol) except adsorbed on O3 atom. CO₂ is found to favorably adsorb in a linear configuration, in which CO₂ has an electrostatic attraction with the Ca atom in type $A$, the CO₂ carbon atom forms a new chemical bond with oxygen of anorthite surface in type $B$. In this group, the CO₂ is bent into $V$ shape with the O–C–O angle decreased and a significant elongation of the C–O bond length compared with the free CO₂ molecule. Mulliken charge population analyses were implemented to indicate charge transfer from the anorthite (001) surface to the CO₂ molecule. The partial density of states (PDOS) analysis of stable configurations further explains the strong interactions between CO₂ and anorthite (001) surface. The existence of H₂O molecule performs a positive influence on the adsorption of CO₂ with significant decrease of the adsorption energy.

The Raman (50–3500cm${}^{-1}$) and infrared (200–3500cm${}^{-1}$) spectra of (2Z,4Z)-Hexa-2,4-dienedinitrile (C₆H₄N₂; cis,cis-HDDN) have been recorded. Initially, three conformers were proposed based on following point groups: C_2h, C_2v and ${\text{C}}_2$ (gauche). For comparison purposes, M05-2X, M06-2X method were used in addition to B3LYP, MP2$=$full and MP4$=$full quantum mechanical calculations employing 6-31G(d) and 6-311+G(d,p) basis sets using Gaussian 09 program. Aided by potential energy surface scan, the C_2h conformer is verified as a global minimum and the gauche (${\text{C}}_2$) being a local minimum with an energy barrier of 2.82kcal/mol. The energy difference ranged from 4.87 to 13.70kcal/mol favors the C_2h conformer in good agreement with Raman and infrared spectral analysis. These results were also supported by the observed $J$ value (H₉-H${}_{10}$) at 10.8Hz which is consistent to 10.19Hz estimated for centrosymmetric conformer (C_2h) rather than 4.81Hz predicted for gauche (${\text{C}}_2$). Complete vibrational assignments are proposed herein based on normal coordinate analysis (NCA) and potential energy distributions (PEDs) combined with theoretical vibrational frequencies and force constants in internal coordinates. It is crucial that NCA using VEDA 4 program with mixing shows large deviations from ours due to neglecting symmetry elements while mixing molecular vibrational motions. The results of these spectroscopic and theoretical studies are reported herein and compared with similar molecules whenever appropriate.

The conformation of five-membered furanose rings is a crucial issue for the structural analysis of many biologically-relevant molecules, including DNA and RNA. Oxolane can be treated as a prototypical furanose, composed only of saturated unsubstituted ring. In spite of its structural simplicity, providing the accurate quantitative description of the oxolane conformational features remains a great challenge for both the experimental and theoretical techniques. Here we show the method of recovering the free-energy profiles describing the conformational equilibrium in the oxolane ring (i.e. pseudorotation) based on the experimentally-inferred NMR data (${}^3{\text{J}}_{\text{H},\text{H}}$ coupling constants). The results remain in agreement with the quantum-mechanical-based molecular dynamics simulations and emphasize the large contributions of all ring conformers, even those located at the free-energy barriers. This includes the significant populations of limiting ³T₂/²T₃ and ^OE/E_O shapes. Our findings provide another example of a poor applicability of the two-state model, which is routinely applied to analyze the NMR data in terms of population of different ring conformers.

The noncrossing rule for potential energy surfaces can be applied only, as originally postulated by von Neumann and Wigner, to slowly occurring changes; it has, however, over many years, been widely used to rationalize fast chemical reactions. Taking the conversion of Dewar benzene to benzene as an example, we demonstrate a reaction that has a timescale for which crossings are allowed. Since it is now established that elementary chemical reactions proceed over ca. 10–100fs, as revealed experimentally by Zewail, the noncrossing rule cannot any longer be said to be valid for most chemical reactions. We further demonstrate that the mechanism of the chemiluminescent conversion of Dewar benzene to benzene is explained by an electronic state diagram derived using a dynamic correlation diagram method which allows crossings, whereas the reaction is not explained by a conventional approach, applying the noncrossing rule using a static correlation diagram method.