Excited-state proton-transfer reactions of 7-azaindole with water, ammonia and mixed water–ammonia: microsolvated dynamics simulation

<div><p>Dynamics simulations of excited-state multiple proton transfer (ESMPT) reactions in 7-azaindole (7AI) with ammonia, mixed water–ammonia, and water molecules were investigated by quantum dynamics simulations in the first-excited state using RI-ADC(2)/SVP-SV(P) in the gas phase. 7AI(WW), 7AI(WA), 7AI(AW) and 7AI(AA) clusters (W, water and A, ammonia) show very high probability of the excited-state triple proton transfer (ESTPT) occurrence in ranges from 20% for 7AI(WA) to 60% for 7AI(AW), respectively. Furthermore, 7AI(AW) clusters with ammonia placed near N–H of 7AI has the highest probability among other isomers. In 7AI with three molecules of bridged-planar of water, ammonia and mixed water–ammonia clusters, the excited-state quadruple proton transfer reactions occur ineffectively and rearrangement of hydrogen-bonded network on solvents also takes place prior to either ESTPT or excited-state double proton transfer. The role played by mixed-solvent is revealed with replacing H₂O with NH₃ in which the ESMPT is found to be more efficient corresponding to lower barrier in the excited state. The preferential number of solvent surrounding 7AI that facilitates the proton transfer process is two for methanol and water but this preferential number for ammonia is one.</p><p>Highlights: (i) replacing H₂O with NH₃ assists ESPT corresponding to lower barrier in the excited state; (ii) the ESMPT time of 7AI with mixed water–ammonia is in the sub-picosecond timescale; (iii) the PT tends to be concerted process with at least one ammonia, but synchronous without ammonia.</p></div

Theoretical Insight into Catalytic Propane Dehydrogenation on Ni(111)

Here, propane dehydrogenation (PDH) to propylene and side reactions, namely, cracking and deep dehydrogenation on Ni(111) surface, have been theoretically investigated by density functional theory calculation. On the basis of adsorption energies, propane is physisorbed on Ni(111) surface, whereas propylene exhibits chemisorption supported by electronic charge results. In the PDH reaction, possible pathways can occur via two possible intermediates, i.e., 1-propyl and 2-propyl. Our results suggest that PDH reaction through 1-propyl intermediate is both kinetically and thermodynamically more favorable than another pathway. The C–C bond cracking during PDH process is more difficult to occur than the C–H activation reaction because of higher energy barrier of the C–C bond cracking. However, deep dehydrogenation is the preferable process after PDH, owing to the strong adsorption of propylene on Ni(111) surface, resulting in low selectivity of propylene production. This work suggests that Ni(111) has superior activity toward PDH; however, the enhancement of propylene desorption is required to improve its selectivity. The understanding in molecular level from this work is useful for designing and developing better Ni-based catalysts in terms of activity and selectivity for propane conversion to propylene

Computational screening of fatty acid synthase inhibitors against thioesterase domain

<p>Thioesterase (TE) domain of fatty acid synthase (FAS) is an attractive therapeutic target for design and development of anticancer drugs. In this present work, we search for the potential FAS inhibitors of TE domain from the ZINC database based on similarity search using three natural compounds as templates, including flavonoids, terpenoids, and phenylpropanoids. Molecular docking was used to predict the interaction energy of each screened ligand compared to the reference compound, which is methyl γ-linolenylfluorophosphonate (MGLFP). Based on this computational technique, rosmarinic acid and its eight analogs were observed as a new series of potential FAS inhibitors, which showed a stronger binding affinity than MGLFP. Afterward, nine docked complexes were studied by molecular dynamics simulations for investigating protein–ligand interactions and binding free energies using MM-PB(GB)SA, MM-3DRISM-KH, and QM/MM-GBSA methods. The binding free energy calculation indicated that the ZINC85948835 (R34) displayed the strongest binding efficiency against the TE domain of FAS. There are eight residues (S2308, I2250, E2251, Y2347, Y2351, F2370, L2427, and E2431) mainly contributed for the R34 binding. Moreover, R34 could directly form hydrogen bonds with S2308, which is one of the catalytic triad of TE domain. Therefore, our finding suggested that R34 could be a potential candidate as a novel FAS-TE inhibitor for further drug design.</p

Microporous, Self-Segregated, Graphenal Polymer Nanosheets Prepared by Dehydrogenative Condensation of Aza-PAHs Building Blocks in the Solid State

A class of porous organic polymers (POPs), which are constructed by aryl–aryl linkages, has the wholly conjugated organic frameworks that can post-transform into two-dimensional graphenal polymers by the intramolecular dehydrogenation. However, typical examples are difficultly defined on the molecular sizes, numbers, and distributions of graphene subunits within the networks, thereby giving rise to uncertainty in applications. Here we report a dehydrogenation fusion of polycyclic aromatic hydrocarbons (PAHs) into graphenal polymers under solvent-free and ionothermal conditions, by which 5,6,11,12,17,18-hexaazatrinaphthylene (HATNA) is linked on itself to expand along the coplanar direction. During the reaction, the catalyst AlCl₃ solids turn into the molten media to homogenize the reaction system, and alter the molecular configuration and reactivity of HATNA units, resulting in the formation of self-segregated nanosheets with the neighboring layers of the weakened π–π interaction. Besides, the obtained framework exhibits the intrinsic microporosity and exceptionally high surface area. We demonstrate that they can well perform on anhydrous proton conduction and catalytic cycloaddition of CO₂ with epoxides. Therefore, this bottom-up strategy may constitute a step toward realizing innovative applications of POPs based on commercially available PAHs

Excited-State Intermolecular Proton Transfer Reactions of 7-Azaindole(MeOH)_<i>n</i> (<i>n</i> = 1–3) Clusters in the Gas phase: On-the-Fly Dynamics Simulation

Ultrafast excited-state intermolecular proton transfer (PT) reactions in 7-azaindole(methanol)_<i>n</i> (<i>n</i> = 1–3) [7AI(MeOH)_{<i>n</i>=1–3}] complexes were performed using dynamics simulations. These complexes were first optimized at the RI-ADC(2)/SVP-SV(P) level in the gas phase. The ground-state structures with the lowest energy were also investigated and presented. On-the-fly dynamics simulations for the first-excited state were employed to investigate reaction mechanisms and time evolution of PT processes. The PT characteristics of the reactions were confirmed by the nonexistence of crossings between S_ππ* and S_πσ* states. Excited-state dynamics results for all complexes exhibit excited-state multiple-proton transfer (ESmultiPT) reactions via methanol molecules along an intermolecular hydrogen-bonded network. In particular, the two methanol molecules of a 7AI(MeOH)₂ cluster assist the excited-state triple-proton transfer (ESTPT) reaction effectively with highest probability of PT

Theoretical Insights on Solvent Control of Intramolecular and Intermolecular Proton Transfer of 2‑(2′-Hydroxyphenyl)benzimidazole

Excited-state proton transfer (ESPT) processes of 2-(2′-hydroxyphenyl)­benzimidazole (HBI) and its complexation with protic solvents (H₂O, CH₃OH, and NH₃) have been investigated by both static calculations and dynamics simulations using density functional theory (DFT) at B3LYP/TZVP theoretical level for ground state (S₀) and time-dependent (TD)-DFT at TD-B3LYP/TZVP for excited state (S₁). For static calculations, absorption and emission spectra, infrared (IR) vibrational spectra of O–H mode, frontier molecular orbitals (MOs), and potential energy curves (PECs) of proton transfer coordinate were analyzed. Simulated absorption and emission spectra show an agreement with available experimental data. The hydrogen bond strengthening in the S₁ state has been proved by the changes of IR vibrational spectra and bond parameters of the hydrogen moiety with those of the S₀ state. The MOs provide the visual electron density redistribution confirming the hydrogen bond strengthening mechanism. The PECs show that the proton transfer (PT) process is easier to occur in the S₁ state than the S₀ state. Moreover, on-the-fly dynamics simulations of all systems were carried out to provide the detailed information on time revolution. The results revealed that the excited-state intermolecular proton transfer for HBI is fast, whereas the excited-state intermolecular proton transfer for HBI with protic solvents are slower than that of HBI because the competition between intra- and intermolecular hydrogen-bonds between HBI and protic solvent. These intermolecular hydrogen-bonds hinder the formation of tautomer, hence explaining the low quantum yield found in the protic solvent experiment. Especially for HBI complexing with methanol, only ESIntraPT occurs with small probability compared to HBI with water and ammonia

Theoretical Insights on Solvent Control of Intramolecular and Intermolecular Proton Transfer of 2‑(2′-Hydroxyphenyl)benzimidazole

Excited-state proton transfer (ESPT) processes of 2-(2′-hydroxyphenyl)­benzimidazole (HBI) and its complexation with protic solvents (H₂O, CH₃OH, and NH₃) have been investigated by both static calculations and dynamics simulations using density functional theory (DFT) at B3LYP/TZVP theoretical level for ground state (S₀) and time-dependent (TD)-DFT at TD-B3LYP/TZVP for excited state (S₁). For static calculations, absorption and emission spectra, infrared (IR) vibrational spectra of O–H mode, frontier molecular orbitals (MOs), and potential energy curves (PECs) of proton transfer coordinate were analyzed. Simulated absorption and emission spectra show an agreement with available experimental data. The hydrogen bond strengthening in the S₁ state has been proved by the changes of IR vibrational spectra and bond parameters of the hydrogen moiety with those of the S₀ state. The MOs provide the visual electron density redistribution confirming the hydrogen bond strengthening mechanism. The PECs show that the proton transfer (PT) process is easier to occur in the S₁ state than the S₀ state. Moreover, on-the-fly dynamics simulations of all systems were carried out to provide the detailed information on time revolution. The results revealed that the excited-state intermolecular proton transfer for HBI is fast, whereas the excited-state intermolecular proton transfer for HBI with protic solvents are slower than that of HBI because the competition between intra- and intermolecular hydrogen-bonds between HBI and protic solvent. These intermolecular hydrogen-bonds hinder the formation of tautomer, hence explaining the low quantum yield found in the protic solvent experiment. Especially for HBI complexing with methanol, only ESIntraPT occurs with small probability compared to HBI with water and ammonia

Comparison of Implicit and Explicit Solvation Models for <i>Iota</i>-Cyclodextrin Conformation Analysis from Replica Exchange Molecular Dynamics

Large ring cyclodextrins have become increasingly important for drug delivery applications. In this work, we have performed replica-exchange molecular dynamics simulations using both implicit and explicit water solvation models to study the conformational diversity of <i>iota</i>-cyclodextrin containing 14 α-1,4 glycosidic linked d-glucopyranose units (CD14). The new quantifiable calculation methods are proposed to analyze the openness, bending, and twisted conformation of CD14 in terms of circularity, biplanar angle, and one-directional conformation (ODC). CD14 in GB implicit water model (Igb5) was found mostly in an opened conformation with average circularity of 0.39 ± 0.16 and a slight bend with average biplanar angle of 145.5 ± 16.0°. In contrast, CD14 in TIP3P explicit water solvation is significantly twisted with average circularity of 0.16 ± 0.10, while 29.1% are ODCs. In addition, classification of CD14 conformations using a Gaussian mixture model (GMM) shows that 85.0% of all CD14 in implicit water at 300 K correspond to the elliptical conformation, in contrast to 82.3% in twisted form in explicit water. GMM clustering also reveals minority conformations of CD14 such as the 8-shape, boat-form, and twisted conformations. This work provides fundamental insights into CD14 conformation, influence of solvation models, and also proposes new quantifiable analysis techniques for molecular conformation studies in the future

Molecular Dynamics Simulation Reveals the Selective Binding of Human Leukocyte Antigen Alleles Associated with Behçet's Disease

<div><p>Behçet’s disease (BD), a multi-organ inflammatory disorder, is associated with the presence of the human leukocyte antigen (HLA) HLA-B*51 allele in many ethnic groups. The possible antigen involvement of the major histocompatibility complex class I chain related gene A transmembrane (MICA-TM) nonapeptide (AAAAAIFVI) has been reported in BD symptomatic patients. This peptide has also been detected in HLA-A*26:01 positive patients. To investigate the link of BD with these two specific HLA alleles, molecular dynamics (MD) simulations were applied on the MICA-TM nonapeptide binding to the two BD-associated HLA alleles in comparison with the two non-BD-associated HLA alleles (B*35:01 and A*11:01). The MD simulations were applied on the four HLA/MICA-TM peptide complexes in aqueous solution. As a result, stabilization for the incoming MICA-TM was found to be predominantly contributed from van der Waals interactions. The P2/P3 residue close to the N-terminal and the P9 residue at the C-terminal of the MICA-TM nonapeptide served as the anchor for the peptide accommodated at the binding groove of the BD associated HLAs. The MM/PBSA free energy calculation predicted a stronger binding of the HLA/peptide complexes for the BD-associated HLA alleles than for the non-BD-associated ones, with a ranked binding strength of B*51:01 > B*35:01 and A*26:01 > A*11:01. Thus, the HLAs associated with BD pathogenesis expose the binding efficiency with the MICA-TM nonapeptide tighter than the non-associated HLA alleles. In addition, the residues 70, 73, 99, 146, 147 and 159 of the two BD-associated HLAs provided the conserved interaction for the MICA-TM peptide binding.</p></div

Structural basis of HLA class I.

<p>(A) Schematic model of HLA buried in the transmembrane. (B) HLA (pink) contains the <i>α</i>1 and <i>α</i>2 subdomains that contribute to the peptide binding groove, while <i>α</i>3 is the C-terminal domain in complex with <i>ß</i>₂-microgluobulin (<i>ß</i>₂m) as a noncovalently supported protein (cyan). (C) Ribbon and (D) van der Waals surface representations of the MICA-TM nonapeptide (green stick model) occupied in the peptide binding sub-sites (S1–S9, shaded by different colors) of HLA-B*51:01.</p