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1.
J Chem Inf Model ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32053358

RESUMO

Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Motivated by that inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for the design of anticancer drugs, we carried out metadynamics simulations to study the coupled folding and binding process linking the IDP p53 to MDM2 in atomic detail. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD) we estimated the binding free energy, the unbinding rate and the binding rate. By analyzing the stable intermediates, we uncovered the role of nonnative interactions played in the p53-MDM2 binding/unbinding process. We used a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced fit mechanism which proceeds in a stepwise fashion. Our results can be helpful for the in-depth understanding of the coupled folding and binding process needed for the design of MDM2 inhibitors.

2.
Chemistry ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052498

RESUMO

This work describes a synthetic approach where a non-planar aromatic heterocyclic [7]helicene is compressed to yield a hetero[8]circulene containing an inner antiaromatic cyclooctatetraene (COT) core. This [8]circulene consists of four benzene rings and four heterocyclic rings, and it is the first heterocyclic [8]circulene containing three different heteroatoms. The synthetic pathway proceeds via a the flattened dehydro-hetero[7]helicene, which is partially a helicene and partially a circulene: it is non-planar and helically chiral as helicenes, and contains a COT motif like [8]circulenes. The antiaromaticity of the COT core is confirmed by nucleus independent chemical shift (NICS) calculations. The planarization from a helically p-conjugated [7]helicene to a fully planar heterocyclic [8]circulene significantly alters the spectroscopic properties of the molecules. Post-functionalization of the [7]helicenes and the [8]circulenes by oxygenation of the thiophene rings to the corresponding thiophene-sulfones allows an almost complete fluorescence emission coverage of the visible region of the optical spectrum (400-700 nm).

3.
Artigo em Inglês | MEDLINE | ID: mdl-31961984

RESUMO

We present a high yielding intramolecular oxidative coupling within a diazadioxa[10]helicene to give a dihydro-diazatrioxa[9]circulene. This is the first [n]circulene containing more the eight ortho annulated rings (n>8). The single crystal X-ray structure reveals a tight columnar packing, with a proton from a pendant naphthalene moiety centred directly above the central 9-membered ring. This distinct environment induces a significant magnetic deshielding effect on that particular proton as determined by 1 H-NMR spectroscopy. The origin of the deshielding effect is investigated computationally by NICS values. It is established that the deshielding effect originates from an induced paratropic ring current from the seven aromatic rings of the [9]circulene structure, and not due to the nine-membered ring being antiaromatic. UV/vis spectroscopy reveals efficient conjugation in the prepared diazatrioxa[9]circulene compared to the parent helical azaoxa[10]helicenes, and DFT calculations, including energy levels, confirm the experimental observations.

4.
Small ; : e1906475, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31994360

RESUMO

Organic luminogens constitute promising prototypes for various optoelectronic applications. Since gaining distinct color emissions normally requires the alternation of the conjugated backbone, big issues remain in material synthetic cost and skeleton compatibility while pursuing full-color luminescence. Upon a facile one-step coupling, three simple but smart perchalcogenated (O, S, and Se) arenes are synthesized. They exhibit strong luminescent tricolor primaries (i.e., blue, green, and red, respectively) in the solid state with a superior quantum yield up to >40% (5-10 times higher than that in corresponding solutions). The properties originate from a fluorescence-phosphorescence-phosphorescence triple-channel emission effect, which is regulated by S and Se heavy atoms-dependent intersystem crossing upon molecular packing, as well as Se-Se atom interaction-caused energy splittings. Consequently, full-color luminescence, including a typical white-light luminescence with a Commission Internationale de I'Eclairage coordinate of (0.30, 0.35), is realized by complementarily incorporating these tricolor luminescent materials in the film. Moreover, mechanochromic luminescent color conversions are also observed to achieve the fine-tuning of the luminescent tints. This strategy can be smart to address full-color luminescence on the same molecular skeleton, showing better material compatibility as an alternative to the traditional multiple-luminophore engineering.

5.
Angew Chem Int Ed Engl ; 59(4): 1537-1541, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31709678

RESUMO

An N-confused phlorin isomer bearing a dipyrrin moiety at the α-position of the confused pyrrole ring (1) was synthesized. PdII and BIII coordination at the peripheral prodigiosin-like moiety of 1 afforded the corresponding complexes 2 and 3. Reflux of 2 in triethylamine (TEA) converted the meso-phenyl into the PdII -coordinating phenoxy group to afford 4. Under the same reaction conditions, TEA was linked to the α-position of the dipyrrin unit in 3 as an N,N-diethylaminovinyl group to afford 5. Furthermore, peripheral coordination of BIII in 3 and 5 improved the planarity of the phlorin macrocycle and thus facilitated the coordination of AgIII at the inner cavity to afford 3-Ag and 5-Ag, respectively. These results provide an effective approach for developing unique porphyrinoids through peripheral coordination.

6.
J Phys Chem Lett ; 10(22): 7086-7092, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31665886

RESUMO

Single- and few-layer black phosphorus possesses interesting properties suitable for various optoelectronic applications where graphene cannot be applied due to its vanishing band gap. As phosphorene tends to degrade in environments, various approaches including fluorination have been explored to passivate its surface. Several structures of fluorinated phosphorene have thus recently been reported to demonstrate this approach. On the basis of a combination of first-principles electronic structure calculations and ab initio molecular dynamics, we reconsider the structure of fluorinated phosphorene marking previously reported configurations as thermodynamically unstable with a tendency to decompose spontaneously. We reveal the mechanism of fluorination and propose novel thermodynamically and energetically stable structures containing double fluorine units with enhanced antioxidative stability caused by the fluorination-induced negative electrostatic potential on the surface of phosphorene. The partially fluorinated structure demonstrates almost the same band gap compared to bare phosphorene, making it possible to utilize them in nano-optoelectronic applications.

7.
Phys Chem Chem Phys ; 21(45): 25334-25343, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701970

RESUMO

The recently synthesized twisted thia-norhexaphyrin and its multiply annulated polypyrrolic derivatives have been studied computationally. Gauge-including magnetically induced current calculations predict a global nonaromatic character of the initial thia-norhexaphyrin due to the highly-twisted conformation of the macrocycle. Upon the oxidation of the thia-norhexaphyrin four multiply annulated polypyrrolic aromatic macrocycles are formed for which the global aromatic character is confirmed in agreement with experimentally measured 1H NMR spectra. The calculation of the proton chemical shifts for the studied compounds by direct comparison with the tetramethylsilane standard leads to a significant mean absolute error. At the same time a linear regression procedure for the two selected groups of protons (CH and NH protons) provides much better values of calculated chemical shifts and tight correlation with experiment. The separate consideration of NH protons is motivated by the numerous intermolecular hydrogen bonds in which the protons are involved, which induce considerable upfield shifts, leading to a significant underestimation of the corresponding chemical shifts. Such a selected correlation can be used for accurate estimation of proton chemical shifts of the related porphyrinoids. Bader's theory of Atoms in Molecules has been applied for the studied twisted thia-norhexaphyrin and its multiply annulated polypyrrolic derivatives to characterize intramolecular H-bonds and other non-covalent interactions.

8.
J Phys Chem Lett ; 10(21): 6701-6705, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609631

RESUMO

Cyclo[18]carbon (C18) is studied computationally at the density functional theory (DFT) and ab initio levels to obtain insight into its electronic structure, aromaticity, and adsorption properties on a NaCl surface. DFT functionals with a small amount of Hartree-Fock exchange fail to determine the experimentally observed polyyne molecular structure, revealing a cumulene-type geometry. Exchange-correlation functionals with a large amount of Hartree-Fock exchange as well as ab initio CASSCF calculations yield the polyyne structure as the ground state and the cumulene structure as a transition state between the two inverted polyyne structures through a Kekule distortion. The polyyne and the cumulene structures are found to be doubly Hückel aromatic. The calculated adsorption energy of cyclo[18]carbon on the NaCl surface is small (37 meV/C) and almost the same for both structures, implying that the surface does not stabilize a particular geometry.

9.
J Chem Inf Model ; 59(9): 3910-3918, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31454236

RESUMO

Understanding unbinding kinetics of protein-ligand systems is of great importance for the design of ligands with desired specificity and safety. In recent years, enhanced sampling techniques have emerged as effective tools for studying unbinding kinetics of protein-ligand systems at the atomistic level. However, in many protein-ligand systems, the ligand unbinding processes are strongly coupled to protein conformational changes and the disclosure of the hidden degrees of freedom closely related to the protein conformational changes so that sampling is enhanced over these degrees of freedom remains a great challenge. Here, we show how potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) simulation techniques can be combined to successfully reveal the unbinding mechanism of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluo-rodibenzo[b,d]thiophene 5,5-dioxide ([18F]ASEM) from a chimera structure of the α7-nicotinic acetylcholine receptor. By using sMD simulations, we disclosed that the "close" to "open" conformational change of loop C plays a key role in the ASEM unbinding process. By carrying out InMetaD simulations with this conformational change taken into account as an additional collective variable, we further captured the key states in the unbinding process and clarified the unbinding mechanism of ASEM from the protein. Our work indicates that combining sMD and InMetaD simulation techniques can be an effective approach for revealing the unbinding mechanism of a protein-ligand system where protein conformational changes control the unbinding process.

10.
Nanoscale ; 11(29): 14070-14078, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31313798

RESUMO

The dearth of high upconversion luminescence (UCL) intensity at low excitation irradiance hinders the prevalent application of lanthanide-doped upconversion nanoparticles (UCNPs) in many fields ranging from optical bioimaging to photovoltaics. In this work, we propose to use microlens arrays (MLAs) as spatial light modulators to manipulate the distribution of excitation light fields in order to increase UCL, taking advantage of its nonlinear response to the excitation irradiance. We show that multicolored UCL from NaYF4:Yb3+,Er3+@NaYF4:Yb3+,Nd3+ and NaYF4:Yb3+,Tm3+@NaYF4:Yb3+,Nd3+ core/shell UCNPs can be increased by more than one order of magnitude under either 980 or 808 nm excitation, by simply placing a polymeric MLA onto the top of these samples. The observed typical green (525/540 nm) and red (654 nm) UCL bands from Er3+ and a blue (450/475 nm) UCL band from Tm3+ exhibit distinct enhancement factors due to their different multi-photon processes. Importantly, our ray tracing simulation reveals that the MLA is able to spatially confine the excitation light (980 and 808 nm) by orders of magnitude, thus amplifying UCL by more than 225-fold (the 450 nm UCL band of Tm3+) at low excitation irradiance. The proposed MLA method has immediate ramifications for the improved performance of all types of UCNP-based devices, such as UCNP-enhanced dye sensitized solar cells demonstrated here.

11.
J Chem Phys ; 150(23): 234301, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31228920

RESUMO

We report on a combined theoretical and experimental study of core-excitation spectra of gas and liquid phase methanol as obtained with the use of X-ray absorption spectroscopy (XAS) and resonant inelastic X-ray scattering (RIXS). The electronic transitions are studied with computational methods that include strict and extended second-order algebraic diagrammatic construction [ADC(2) and ADC(2)-x], restricted active space second-order perturbation theory, and time-dependent density functional theory-providing a complete assignment of the near oxygen K-edge XAS. We show that multimode nuclear dynamics is of crucial importance for explaining the available experimental XAS and RIXS spectra. The multimode nuclear motion was considered in a recently developed "mixed representation" where dissociative states and highly excited vibrational modes are accurately treated with a time-dependent wave packet technique, while the remaining active vibrational modes are described using Franck-Condon amplitudes. Particular attention is paid to the polarization dependence of RIXS and the effects of the isotopic substitution on the RIXS profile in the case of dissociative core-excited states. Our approach predicts the splitting of the 2a″ RIXS peak to be due to an interplay between molecular and pseudo-atomic features arising in the course of transitions between dissociative core- and valence-excited states. The dynamical nature of the splitting of the 2a″ peak in RIXS of liquid methanol near pre-edge core excitation is shown. The theoretical results are in good agreement with our liquid phase measurements and gas phase experimental data available from the literature.

12.
Front Neurosci ; 13: 351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068774

RESUMO

Reproducibly generating human induced pluripotent stem cell-based functional neuronal circuits, solely obtained from single individuals, poses particular challenges to achieve personalized and patient specific functional neuronal in vitro models. A hallmark of functional neuronal assemblies, synchronous neuronal activity, can be non-invasively studied by microelectrode array (MEA) technology, reliably capturing physiological and pathophysiological aspects of human brain function. In our here presented manuscript, we demonstrate a procedure to generate 3D neural aggregates comprising astrocytes, oligodendroglial cells, and neurons obtained from the same human tissue sample. Moreover, we demonstrate the robust ability of those neurons to create a highly synchronously active neuronal network within 3 weeks in vitro, without additionally applied astrocytes. The fusion of MEA-technology with functional neuronal circuits solely obtained from one individual's cells represent isogenic person-specific human neuronal sensor chips that pave the way for specific personalized in vitro neuronal networks as well as neurological and neuropsychiatric disease modeling.

13.
J Phys Chem B ; 123(17): 3776-3785, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30964991

RESUMO

The distribution and protonation states of amino acids in water droplets are of considerable concern in studies on the formation of clouds in the atmosphere as well as in many biological contexts. In the present work we use the amino acid cysteine as a prototypical example and explore the protonation states of this molecule in aqueous solution, which are strongly affected by the acidity of the environment and also can show different distributions between surface and bulk. We use a combination of X-ray photoelectron chemical shift measurements, density functional theory calculations of the shifts, and reactive force field molecular dynamics simulations of the underlying structural dynamics. We explore how the photoelectron spectra distinctly reflect the different protonation states that are generated by variation of the solution acidity and how the distribution of these protonation states can differ between bulk and surface regions. At specific pH values, we find that the distribution of the cysteine species at the surface is quite different from that in bulk, in particular, for the appearance in the surface region of species which do not exist in bulk. Some ramifications of this finding are discussed.

14.
Eur J Nucl Med Mol Imaging ; 46(6): 1369-1382, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919054

RESUMO

PURPOSE: Several tracers have been designed for tracking the abnormal accumulation of tau pathology in vivo. Recently, concerns have been raised about the sources of off-target binding for these tracers; inconclusive data propose binding for some tracers to monoamine oxidase B (MAO-B). METHODS: Molecular docking and dynamics simulations were used to estimate the affinity and free energy for the binding of several tau tracers (FDDNP, THK523, THK5105, THK5317, THK5351, T807 [aka AV-1451, flortaucipir], T808, PBB3, RO-948, MK-6240, JNJ-311 and PI-2620) to MAO-B. These values were then compared with those for safinamide (MAO-B inhibitor). PET imaging was used with the tau tracer [18F]THK5317 and the MAO-B tracer [11C]DED in five patients with Alzheimer's disease to investigate the MAO-B binding component of this first generation tau tracer in vivo. RESULTS: The computational modelling studies identified a binding site for all the tau tracers on MAO-B; this was the same site as that for safinamide. The binding affinity and free energy of binding for the tau tracers to MAO-B was substantial and in a similar range to those for safinamide. The most recently developed tau tracers MK-6240, JNJ-311 and PI-2620 appeared, in silico, to have the lowest relative affinity for MAO-B. The in vivo investigations found that the regional distribution of binding for [18F]THK5317 was different from that for [11C]DED, although areas of suspected off-target [18F]THK5317 binding were detected. The binding relationship between [18F]THK5317 and [11C]DED depended on the availability of the MAO-B enzyme. CONCLUSIONS: The developed tau tracers show in silico and in vivo evidence of cross-interaction with MAO-B; the MAO-B component of the tracer binding was dependent on the regional concentration of the enzyme.

15.
Nanoscale ; 11(11): 4959-4969, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30839016

RESUMO

In this study, we systematically investigate the decay characteristics of upconversion luminescence (UCL) under anti-Stokes excitation through numerical simulations based on rate-equation models. We find that a UCL decay profile generally involves contributions from the sensitizer's excited-state lifetime, energy transfer and cross-relaxation processes. It should thus be regarded as the overall temporal response of the whole upconversion system to the excitation function rather than the intrinsic lifetime of the luminescence emitting state. Only under certain conditions, such as when the effective lifetime of the sensitizer's excited state is significantly shorter than that of the UCL emitting state and of the absence of cross-relaxation processes involving the emitting energy level, the UCL decay time approaches the intrinsic lifetime of the emitting state. Subsequently, Stokes excitation is generally preferred in order to accurately quantify the intrinsic lifetime of the emitting state. However, possible cross-relaxation between doped ions at high doping levels can complicate the decay characteristics of the luminescence and even make the Stokes-excitation approach fail. A strong cross-relaxation process can also account for the power dependence of the decay characteristics of UCL.

16.
Angew Chem Int Ed Engl ; 58(18): 5925-5929, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-30843636

RESUMO

A hybrid thia-norhexaphyrin comprising a directly linked N-confused pyrrole and thiophene unit (1) revealed unique macrocycle transformations to afford multiply inner-annulated aromatic macrocycles. Oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone triggered a cleavage of the C-S bond of the thiophene unit, accompanied with skeletal rearrangement to afford unique π-conjugated products: a thiopyrrolo-pentaphyrin embedded with a pyrrolo[1,2]isothiazole (2), a sulfur-free pentaphyrin incorporating an indolizine moiety (3), and a thiopyranyltriphyrinoid containing a 2H-thiopyran unit (4). Furthermore, 2 underwent desulfurization reactions to afford a fused pentaphyrin containing a pyrrolizine moiety (5) under mild conditions. Using expanded porphyrin scaffolds, oxidative thiophene cleavage and desulfurization of the hitherto unknown N-confused core-modified macrocycles would be a practical approach for developing unique polypyrrolic aromatic macrocycles.

17.
J Am Chem Soc ; 141(13): 5294-5302, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30849868

RESUMO

Expanded porphyrins have been attracting increasing attention owing to their unique optical and electrochemical properties as well as switchable aromaticity. Toward material applications, regioselective functionalization of the expanded porphyrins at their periphery is indeed challenging due to the presence of multiple reactive sites. Herein, a set of regioselective halogenated isomers (L5-Br-A/B/C) of neo-confused isosmaragdyrin (L5) are synthesized by a combination of the halogenation reaction of L5 and sequential macrocycle-to-macrocycle transformation reactions of its halogenated isomers. On this basis, the regioselectively functionalized isosmaragdyrins are utilized as building blocks for constructing multichromophoric porphyrinoids, specifically, heterodyads L5-ZnP-A/B/C, in which a common zinc porphyrin is linked at three different pyrrolic positions of isosmaragdyrins, respectively, by Sonogashira coupling reactions. The highly efficient energy cascade from porphyrin to isosmaragdyrin is elucidated using steady-state/time-resolved spectroscopies and theoretical calculations. Notably, the energy transfer processes from the porphyrin to the isosmaragdyrin moieties as well as the excitation energy transfer rates in L5-ZnP-A/B/C are highly dependent on the linking sites by through-bond and Förster-type resonance energy transfer mechanisms. The site-selective functionalization and subsequent construction of a set of heterodyads of the expanded porphyrinoid would provide opportunities for developing new materials for optoelectronic applications.

18.
Proc Natl Acad Sci U S A ; 116(11): 4877-4882, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30733297

RESUMO

Observing and controlling molecular motion and in particular rotation are fundamental topics in physics and chemistry. To initiate ultrafast rotation, one needs a way to transfer a large angular momentum to the molecule. As a showcase, this was performed by hard X-ray C1s ionization of carbon monoxide accompanied by spinning up the molecule via the recoil "kick" of the emitted fast photoelectron. To visualize this molecular motion, we use the dynamical rotational Doppler effect and an X-ray "pump-probe" device offered by nature itself: the recoil-induced ultrafast rotation is probed by subsequent Auger electron emission. The time information in our experiment originates from the natural delay between the C1s photoionization initiating the rotation and the ejection of the Auger electron. From a more general point of view, time-resolved measurements can be performed in two ways: either to vary the "delay" time as in conventional time-resolved pump-probe spectroscopy and use the dynamics given by the system, or to keep constant delay time and manipulate the dynamics. Since in our experiment we cannot change the delay time given by the core-hole lifetime τ, we use the second option and control the rotational speed by changing the kinetic energy of the photoelectron. The recoil-induced rotational dynamics controlled in such a way is observed as a photon energy-dependent asymmetry of the Auger line shape, in full agreement with theory. This asymmetry is explained by a significant change of the molecular orientation during the core-hole lifetime, which is comparable with the rotational period.

19.
Nanomaterials (Basel) ; 9(2)2019 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-30704092

RESUMO

Although all-inorganic CsPbX3 (X = Cl, Br, I) perovskite quantum dots (PQDs) have evoked exciting new opportunities for optoelectronic applications due to their remarkable optical properties, their emission color tunability has not been investigated to any appreciable extent. In this work, double/triple CsPbX3 perovskite quantum dots with precise ratios of Cl/Br or Br/I are synthesized and their luminescence (410⁻700 nm) is explored. A group of down-converted CsPbX3 (X = Cl, Br, I) perovskite quantum dot light-emitting diode (LED) devices were constructed to demonstrate the potential use of such double/triple-halide CsPbX3 perovskite quantum dots with full-spectrum luminescence. Based on density functional theory, we theoretically explored the properties of CsPbX3 with double/triple anion atoms. The calculated band gaps provided strong support that the full-spectrum luminescence (410⁻700 nm) of double/triple CsPbX3 can be realized with the change of the mixed-halide ratios, and hence that such PQDs are of potential use in optoelectronic devices.

20.
Angew Chem Int Ed Engl ; 58(13): 4328-4333, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30706599

RESUMO

Crystal-state luminophores have been of great interest in optoelectronics for years, whereas the excited state regulation at the crystal level is still restricted by the lack of control ways. We report that the singlet-triplet emissive property can be profoundly regulated by crystal conformational distortions. Employing fluoro-substituted tetrakis(arylthio)benzene luminophores as prototype, we found that couples of molecular conformations formed during different crystallizations. The deformable carbon-sulphur bond essentially drove the distortion of the molecular conformation and varied the stacking mode, together with diverse non-covalent interactions, leading to the proportional adjustment of the fluorescence and phosphorescence bands. This intrinsic strategy was further applied for solid-state multicolor emissive conversion and mechanoluminescence, probably offering new insights for design of smart crystal luminescent materials.

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