RESUMO
The electronic and vibrational cryogenic ion spectroscopy of protonated tryptophan (TrpH+) and dopamine (DAH+) complexed with methanol has been recorded. These two biological chromophores exhibit ultrafast photochemistry due to excited-state proton transfer (ESPT). We have established the relationship between the structure of the complexes and their photodynamics and compared them with recent results obtained in hydrated complexes. For TrpH+, there is no substantial change between methanol and water complexes; ESPT is hindered by a single solvent molecule. In the DAH+(MeOH)1 complex, the most stable conformer adopts a structure that prevents the direct interaction of the ammonium group of the side chain with the catechol ring, thus blocking the ESPT reaction. Such a ring structure is indeed a very minor populated conformer in the single-hydrated complex. The change in conformal stability between water and methanol clusters is due to a weak CH-π attractive interaction of the methyl group of methanol with the catechol.
Assuntos
Dopamina , Metanol , Prótons , Triptofano , Metanol/química , Triptofano/química , Dopamina/química , Solventes/química , Água/químicaRESUMO
The gas phase protonation sites of six naturally occurring nicotinoids, namely nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), cotinine (COT), and myosmine (MYO), consisting of a common Pyridine and differing non-Pyridine rings, have been determined for the first time at the physiological temperature from cryogenic ion trap infrared spectroscopy and electronic structure calculations. The protonation site on either of these two rings is related to the nicotinoid's biological activity. At room temperature, NIC is a mixture of Pyridine and Pyrrolidine (non-Pyridine) protomers, whereas NOR, ANB, ANT, and COT are pure Pyridine protomers and finally MYO is mostly a Pyroline (non-Pyridine) protomer. The nearly planar structure of MYO-H+, induced by the presence of a conjugated π system and confirmed from calculations and the UV absorption spectra, breaks from the trends observed for NIC, NOR, and ANB, since its structure is drastically different from the structures of the other nicotinoids.
Assuntos
Gases , Prótons , Gases/química , Estrutura Molecular , Nicotina/química , Nicotina/análogos & derivadosRESUMO
The binding affinity of nicotinoids to the binding residues of the α4ß2 variant of the nicotinic acetylcholine receptor (nAChR) was identified as a strong predictor of the nicotinoid's addictive character. Using ab initio calculations for model binding pockets of increasing size composed of 3, 6, and 14 amino acids (3AA, 6AA, and 14AA) that are derived from the crystal structure, the differences in binding affinity of 6 nicotinoids, namely, nicotine (NIC), nornicotine (NOR), anabasine (ANB), anatabine (ANT), myosmine (MYO), and cotinine (COT) were correlated to their previously reported doses required for increases in intracranial self-stimulation (ICSS) thresholds, a metric for their addictive function. By employing the many-body decomposition, the differences in the binding affinities of the various nicotinoids could be attributed mainly to the proton exchange energy between the pyridine and non-pyridine rings of the nicotinoids and the interactions between them and a handful of proximal amino acids, namely Trp156, Trpß57, Tyr100, and Tyr204. Interactions between the guest nicotinoid and the amino acids of the binding pocket were found to be mainly classical in nature, except for those between the nicotinoid and Trp156. The larger pockets were found to model binding structures more accurately and predicted the addictive character of all nicotinoids, while smaller models, which are more computationally feasible, would only predict the addictive character of nicotinoids that are similar to nicotine. The present study identifies the binding affinity of the guest nicotinoid to the host binding pocket as a strong descriptor of the nicotinoid's addiction potential, and as such it can be employed as a fast-screening technique for the potential addiction of nicotine analogs.
Assuntos
Encéfalo , Receptores Nicotínicos , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Humanos , Sítios de Ligação , Encéfalo/metabolismo , Nicotina/química , Nicotina/análogos & derivados , Nicotina/metabolismo , Anabasina/química , Anabasina/metabolismo , Anabasina/análogos & derivados , Modelos Moleculares , Ligação Proteica , Piridinas/química , Piridinas/metabolismo , Cotinina/química , Cotinina/metabolismo , Cotinina/análogos & derivados , AlcaloidesRESUMO
Proton transfer (PT) is one of the most ubiquitous reactions in chemistry and life science. The unique nature of PT has been rationalized not by the transport of a solvated proton (vehicle mechanism) but by the Grotthuss mechanism in which a proton is transported to the nearest proton acceptor along a hydrogen-bonded network. However, clear experimental evidence of the Grotthuss mechanism has not been reported yet. Herein we show by infrared spectroscopy that a vehicle-type PT occurs in the penta- and hexahydrated clusters of protonated p-aminobenzoic acid, while Grotthuss-type PT is observed in heptahydrated clusters, indicating a change in the PT mechanism depending on the degree of hydration. These findings emphasize the importance of the usually ignored vehicle mechanism as well as the degree of hydration. It highlights the possibility of controlling the PT mechanism by the number of water molecules in chemical and biological environments.
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A π-type hydrogen bonding between the OH group and the π electron is a crucial factor for the conformational preference of the molecular structure with a flexible group. However, the information on the effect of the substituent on the OH/π interaction is insufficient. The laser-induced fluorescence (LIF) excitation, the dispersed fluorescence (DF), the IR-UV hole-burning, and the IR dip spectra of jet-cooled 2-(4-methoxyphenyl)ethanol were measured for the first time. Almost all bands observed in the spectral region of 35 550-36 500 cm-1 in the LIF excitation spectrum were successfully assigned with the DF and the IR-UV hole-burning spectra coupled with the quantum chemical calculation at M06-2x/6-311G and MP2/6-311G levels. Five conformers were found in the LIF excitation spectrum. The most stable conformer was Ggπ, and the second most stable conformer was Ggπ' (the trans rotamer of the methoxy group for Ggπ). Ggπ and Ggπ' had the OH group directed toward the π electron system of the benzene ring. The OH stretching frequency of Ggπ/Ggπ' of MPE in the IR dip spectra was red-shifted against that of Ggπ of phenylethanol, indicating that the introduction of the methoxy group would enhance the intramolecular OH/π interaction. In addition, the torsional vibration between the benzene ring and the side chain (-CH2CH2OH) (mode 63) was observed in the DF spectra of the Ggπ-00 and Ggπ'-00 band excitation, but their intensities were rather different, resulting from the different orientation of the OH group for each conformer toward the π electron system. The methoxy group would increase the negative charge on the benzene ring and would enhance the intramolecular OH/π interaction through the electrostatic interaction.
RESUMO
The switching of the protonation sites in hydrated nicotine, probed by experimental infrared (IR) spectroscopy and theoretical ab initio calculations, is facilitated via a Grotthuss instead of a bimolecular proton transfer (vehicle) mechanism at the experimental temperature (T = 130 K) as unambiguously confirmed by experiments with deuterated water. In contrast, the bimolecular vehicle mechanism is preferred at higher temperatures (T = 300 K) as determined by theory. The Grotthuss mechanism for the concerted proton transfer results in the production of nicotine's bioactive and addictive pyrrolidine-protonated (Pyrro-H+) protomer with just 5 water molecules. Theoretical analysis suggests that the concerted proton transfer occurs via hydrogen-bonded bridges consisting of a 3 water molecule "core" that connects the pyridine protonated (Pyri-H+) with the pyrrolidine-protonated (Pyrro-H+) protomers. Additional water molecules attached as acceptors to the hydrogen-bonded "core" bridge result in lowering the reaction barrier of the concerted proton transfer down to less than 6 kcal/mol, which is consistent with the experimental observations.
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With the ongoing climate and energy crises, thermoelectric conversion has slowly emerged as a clean and reliable alternative energy source for small Internet of Things (IoT) devices. Commercially available thermoelectric generators (TEGs) are typically composed of expensive and toxic Bi2Te3-based thermoelectric materials and require complicated and energy-intensive device assembly processes. As an alternative solution, we have developed a Ag- and Cu-chalcogenide-based monolithic TEG using simple, quick, and low-energy-cost device fabrication processes for low-grade waste heat recovery for energy harvesting. We used ductile Ag2S0.55Se0.45 and overstoichiometric Cu2.075Se, both possessing excellent transport properties around room temperature, with a zT value of â¼0.5 at 300 K. By optimizing the device fabrication process, we were successfully able to assemble the monolithic TEGs without any significant Ag- or Cu-ion migration and obtained a dense and robust device. Strategic optimization of the device structure was able to reduce the electrical contact resistance of the device, which resulted in increased power output. A maximum power density of 0.68 mW/cm2 at a ΔT = 30 K was obtained, which is comparable to a similar Bi2Te3-based monolithic TEG. These results show the potential of chalcogenide-based monolithic TEG as a simple and low-cost alternative to Bi2Te3-based TEGs for energy harvesting applications.
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Beauvericin (Bv) is a naturally occurring ionophore that selectively transports ions through cell membranes. However, the intrinsic ion selectivity of Bv for alkaline earth metal ions (M2+) is yet to be established due to inconsistent results from condensed phase experiments. Based on fluorescence quenching rates, Ca2+ appears to be preferred while extraction experiments favor Mg2+. In this study, we apply cold ion trapâinfrared spectroscopy to Bv-M2+ coupled with electrospray ionization mass spectrometry. The mass spectrum shows that Bv favors binding to physiologically active ions Mg2+ and Ca2+ although it can form complexes with all four alkaline earth metal ions. Infrared spectroscopy, as measured by the H2 tag technique, reveals that Bv binds Mg2+ and Ca2+ ions by six carbonyl oxygens in the center of its cavity. This observation is supported by theoretical calculations. Other alkaline earth metal ions are bound by three carbonyl groups at the amide face. This difference in configuration is consistent with the binding preferences for the alkaline earth metal ions.
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The magnesium channel controls Mg2+ concentration in the cell and plays an indispensable role in biological functions. The crystal structure of the Magnesium Transport E channel suggested that Mg2+ hydrated by 6 water molecules is transported through a selection filter consisting of COO- groups on two Asp residues. This Mg2+ motion implies successive pairing with -OOC-R and dissociation mediated by water molecules. For another divalent ion, however, it is known that RCOO-â¯Ca2+ cannot be separated even with 12 water molecules. From this discrepancy, we probe the structure of Mg2+(CH3COO-)(H2O)4-17 clusters by measuring the infrared spectra and monitoring the vibrational frequencies of COO- with the help of quantum chemistry calculations. The hydration by (H2O)6 is not enough to induce ion separation, and partially-separated or separated pairs are formed from 10 water molecules at least. These results suggest that the ion separation between Mg2+ and carboxylate ions in the selection-filter of the MgtE channel not only results from water molecules in their first hydration shell, but also from additional factors including water molecules and protein groups in the second solvation shell of Mg2+.
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Alkali metal complexes of cyclic dipeptide cyclo Tyr-Tyr have been studied under cryogenic ion trap conditions. Their structure was obtained by combining Infra-Red Photo-Dissociation (IRPD) and quantum chemical calculations. The structural motif strongly depends on the relative chirality of the tyrosine residues. For residues of identical chirality, the cation interacts with one amide oxygen and one of the aromatic rings only; the distance between the aromatic rings does not change with the nature of the metal. In contrast, for residues of opposite chirality, the metal cation is located in between the two aromatic rings and interacts with both of them. The distance between the two aromatic rings strongly depends on the metal. Electronic spectra obtained by Ultra Violet Photodissociation (UVPD) spectroscopy and analysis of the UV photo-fragments shed light on the excited state deactivation processes, which depend on both the chirality of the residue and that of the metal ion core. Na+ stands out by the presence of low-lying charge transfer states resulting in the broadening of the electronic spectrum.
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The naturally occurring ionophore valinomycin (VM) selectively transports K+ across the biological membrane, which makes VM a plausible antivirus and antibacterial candidate. The K+ selectivity of VM was rationalized based on a size-matching model despite structural inconsistency between experiments and computations. In this study, we investigated the conformations of the Na+VM complex with 1-10 water molecules using cryogenic ion trap infrared spectroscopy with computational calculations. It shows that the water molecule penetrates the cavity of VM deeply enough to distort the C3-symmetric structure of gas-phase Na+VM, in stark contrast to hydrated clusters of K+VM with C3-symmetric structure, where H2O is located outside the cavity. The high affinity to K+ would be ascribed to minimal hydration-induced structural deformation of K+VM compared to Na+VM. This study highlights a novel cooperative hydration effect on the K+ selectivity and will provide an updated understanding of its ionophoric properties beyond the traditional size-matching model.
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We investigated the coordinated activity patterns of muscles based on cosine tuning in the elderly during an isometric force exertion task. We also clarified whether these coordinated activity patterns contribute to the control of hip and knee joint torque and endpoint force as co-activation. Preferred direction (PD) of activity for each muscle in 10 young and 8 older males was calculated from the lower limb muscle activity during isometric force exertion task in various directions. The covariance of endpoint force (η) was calculated from the exerted force data using a force sensor. Relationship between PD and η was used to examine the effect of muscle co-activation on the control of endpoint force. Co-activation between rectus femoris and semitendinosus/biceps femoris increased with changes in muscle PD. Additionally, the η values were significantly low, suggesting that co-activation of multiple muscles may contribute to endpoint force exertion. The mechanism for cooperative muscle activity is determined by the cosine tuning of the PD of each muscle, which affects the generation of hip and knee joint torque and endpoint force exertion. Co-activation of each muscle's PD changes with age, causing increased muscle co-activation to control torque and force. We demonstrated that co-activation in the elderly is a stabilizer of unsteady joints and a muscle control strategy for cooperative muscle activity.
Assuntos
Músculos Isquiossurais , Articulação do Joelho , Masculino , Humanos , Idoso , Torque , Articulação do Joelho/fisiologia , Extremidade Inferior , Músculo Quadríceps/fisiologia , Músculo Esquelético/fisiologia , Eletromiografia , Contração Isométrica/fisiologia , Articulação do Quadril/fisiologiaRESUMO
Silver and silver ions have a long history of antimicrobial activity and medical applications. Nevertheless, the activity of Ag+ against bacteria, how it enters a cell, has not yet been established. The K+ channel, a membrane protein, is a possible route. The addition of a channel inhibitor (4-aminopyridine) to modulate the Ag+ uptake could support this view. However, the inhibitor enhances the uptake of Ag+, the opposite result. We have applied cold ion trap infrared laser spectroscopy to complexes of Ag+ and Ac-Tyr-NHMe (a model for GYG) which is a portion of the selectivity filter in the K+ channel to consider the question of permeation. With support from quantum chemical calculations, we have determined the stable conformations of the complex. The conformations strongly suggest that Ag+ would not readily permeate the K+ channel. The mechanism of the unexpected enhancement by the inhibitor is discussed.
Assuntos
Canais de Potássio , Prata , Canais de Potássio/química , Espectrofotometria Infravermelho , Peptídeos/metabolismo , ÍonsRESUMO
The sit-to-stand motion is a prerequisite for walking and is therefore frequently performed in daily life. Diseases such as stroke often make performing it challenging. Even the stroke survivors who can stand up, the number of sit-to-stand motions they perform each day is lower than that of healthy adults. The inability of stroke survivors to stand up many times might be due to uneven distribution of mechanical energy expenditure across body parts. However, it was unclear in which body part this mechanical energy expenditure was concentrated, i.e., whether it was due to co-contraction of the paretic limb or compensation by the sound limb. Thus, this study aims to identify which body parts are responsible for mechanical energy expenditure in stroke survivors. Ten stroke survivors and ten healthy adults performed sit-to-stand motion recorded using motion capture cameras. We created a 3-D human model and calculated the mechanical energy expenditure for each joint and segment. The stroke survivors expended more mechanical energy in the affected hip and waist in contrast to the affected knee. Notably, a compensatory relationship for mechanical energy expenditure was observed between adjacent joints on the affected side and not between the affected and sound limbs. This is because stroke survivors may have achieved the sit-to-stand motion by compensating for the distal part with the less impaired proximal part. In addition, the more severe the movement disorders, the more mechanical energy must be expended in the paretic hip to achieve the sit-to-stand motion. These results could contribute to fundamental knowledge about more comfortable daily living in stroke survivors.
Assuntos
Extremidade Inferior , Acidente Vascular Cerebral , Adulto , Humanos , Fenômenos Biomecânicos , Movimento (Física) , Joelho , MovimentoRESUMO
Rhythmic limb multi-joint movement like locomotion is controlled by intralimb coordination. Intralimb coordination changes entail immediate alterations in movement patterns and be related with cerebellum function. Synchronized cerebellum activity has known to modulate the frequency of walking, but not known the effect of only intralimb coordination. The purpose of this study was to reveal the effect of synchronized and unsynchronized cerebellum activity on the coordination of multi-joint movements of the unilateral leg in young and elderly people. To achieve our purpose, we applied synchronized and unsynchronized cerebellum transcranial alternating current stimulation during cyclic unilateral multi-joint movement by visual tracking task. The results showed that the reduction in comprehensive synchrony between targets and movements through trials had no significant differences under all stimulus conditions in young and elderly people. However, the reduction in variation of synchronization through trials was significantly smaller under the synchronized transcranial alternating current stimulation condition in both young and elderly groups. Variation of synchronization was remarkably reduced under the synchronized transcranial alternating current stimulation condition for the elderly group. This study showed that movement-synchronized cerebellum activity contributes to reducing fluctuations in movement synchrony by coordinating unilateral multi-joint movements. Moreover, this reduction was remarkable in the elderly group.
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Articulações , Locomoção , Humanos , Adulto , Idoso , CaminhadaRESUMO
Para-Aminobenzoic acid (PABA) is a benchmark molecule to study solvent-induced proton site switching. Protonation of the carboxy and amino groups of PABA generates O- and N-protomers of PABAH+, respectively. Ion mobility mass spectrometry (IMS) and infrared photodissociation (IRPD) studies have claimed that the O-protomer most stable in the gas phase is converted to the N-protomer most stable in solution upon hydration with six water molecules in the gas-phase cluster. However, the threshold size has remained ambiguous because the arrival time distributions in the IMS experiments exhibit multiple peaks. On the other hand, IRPD spectroscopy could not detect the N-protomer for smaller hydrated clusters because of broad background due to annealing required to reduce kinetic trapping. Herein, we report the threshold size for O â N protomer switching without ambiguity using IR spectroscopy in a double ion trap spectrometer from 1300 to 1800 cm-1. The pure O-protomer is prepared by electrospray, and size-specific hydrated clusters are formed in a reaction ion trap. The resulting clusters are transferred into a second cryogenic ion trap and the distribution of O- and N-protomers is determined by mid-IR spectroscopy without broadening. The threshold to promote O â N protomer switching is indeed five water molecules. It is smaller than the value reported previously, and as a result, its pentahydrated structure does not support the Grotthuss mechanism proposed previously. The extent of O â N proton transfer is evaluated by collision-assisted stripping IR spectroscopy, and the N-protomer population increases with the number of water molecules. This result is consistent with the dominant population of the N-protomer in aqueous solution.
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Valinomycin (VM) is a natural K+-selective ionophore that transports K+ through the cell membrane. VM captures K+ in its central cavity with a C3-symmetric ß-turn-like backbone. Although the binding affinity is drastically decreased for the VM-sodium (Na+VM) complex with respect to K+VM, VM holds relatively high affinity to Rb+ and Cs+. The high affinity for larger ions irrespective of ionic size seems to conflict with the expected optimal size matching model and raises questions on what factors determine ion selectivity. A combination of infrared spectroscopy with supporting computational calculations reveals that VM can accommodate larger Rb+ and Cs+ by flexibly changing its cavity size with the elongation of its folded ß-turn-like backbone. The high affinity to Rb+ and Cs+ can be ascribed to a size-dependent cavity expansion. These findings provide a new perspective on molecular recognition and selectivity beyond the conventional size matching model.
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Potássio , Sódio , Valinomicina/química , Ionóforos , Cátions , Transporte Biológico , Análise EspectralRESUMO
The photodynamics of protonated tryptophan and its mono hydrated complex TrpH+ -H2 O has been revisited. A combination of steady-state IR and UV cryogenic ion spectroscopies with picosecond pump-probe photodissociation experiments sheds new lights on the deactivation processes of TrpH+ and conformer-selected TrpH+ -H2 O complex, supported by quantum chemistry calculations at the DFT and coupled-cluster levels for the ground and excited states, respectively. TrpH+ excited at the band origin exhibits a transient of less than 100â ps, assigned to the lifetime of the excited state proton transfer (ESPT) structure. The two experimentally observed conformers of TrpH+ -H2 O have been assigned. A striking result arises from the conformer-selective photodynamics of TrpH+ -H2 O, in which a single water molecule inserted in between the ammonium and the indole ring hinders the barrierless ESPT reaction responsible for the ultra-fast deactivation process observed in the other conformer and in bare TrpH+ .
Assuntos
Prótons , Triptofano , Triptofano/química , ÁguaRESUMO
Beauvericin (Bv) is a cyclic hexadepsipeptide mycotoxin that selectively transports ions across cell membranes. Characterization of its intrinsic ion affinity has been complicated by different previous results in condensed phases and biological membranes. We report the marked specificity between alkali metal ions by Bv using experimental and computational methods. Mass spectrometry shows Bv readily binds all five alkali ions; however, the complex with Na+ is the most abundant species, indicating a strong binding preference. Gas phase infrared spectroscopy and theoretical calculations show that Li+, K+, Rb+, and Cs+ are coordinated by three amide carbonyl oxygens on the N-methylamino-l-phenylalanyl face. Selectivity for Na+ is achieved as Bv sequesters Na+ in the center of its cavity formed by three amide carbonyl and three ester carbonyl groups, a configuration unique among alkali metal ions. This finding provides insight into the correlation between selectivity and conformation of Bv, essential for development of this mycotoxin.
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Metais Alcalinos , Espectrometria de Massas , Amidas , Análise EspectralRESUMO
Two diastereomers of the protonated diketopiperazine (DKP) dipeptide cyclo(Tyr-Tyr), namely, cyclo(LTyr-LTyr)H+ and cyclo(LTyr-DTyr)H+, are studied in a cryogenic ion trap by means of IR photodissociation spectroscopy combined with quantum chemical calculations. The two diastereomers have similar structures in which one of the rings is folded over the DKP ring and the other one is extended in a trans geometry, allowing a strong OH+···π interaction to take place. This contrasts to the observation of a stacked geometry for neutral cyclo(LTyr-LTyr) only under supersonic expansion conditions that do not exist for cyclo(LTyr-DTyr). In the protonated form, the strength of the OH+···π interaction is different for the two diastereomers, resulting in a â¼110 cm-1 difference in the ν(OH+) frequency and a smaller but clearly identifiable difference in the protonated amide ν(NH) frequency. Stereochemical effects are therefore still evidenced despite the strong perturbation due to the excess charge.