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1.
Harefuah ; 159(1): 88-92, 2020 Feb.
Artículo en Hebreo | MEDLINE | ID: mdl-32048486

RESUMEN

BACKGROUND: The treatment of patients with advanced head and neck cancers requires an extensive oromandibular and craniomaxillofacial resection in many cases. The reconstruction after these extensive resections presents many challenges to the reconstructive surgical team. The purpose of the reconstruction is not only to rehabilitate the physical facial appearance, but also to rehabilitate function, in order to improve future quality of life. To achieve this goal, the use of free tissue reconstruction is often required. The main challenge with osseous free flap reconstruction of the facial bones is the need of perfect alignment at the defect site. The use of different 3D technologies including computerized models and printed 3D stereolithographic models in the preoperative setting improves the accuracy and the outcome of the reconstruction.


Asunto(s)
Neoplasias de Cabeza y Cuello , Procedimientos Quirúrgicos Reconstructivos , Simulación por Computador , Humanos , Calidad de Vida , Resultado del Tratamiento
2.
Hist Philos Life Sci ; 42(1): 5, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31925568

RESUMEN

The advancement of computing technology makes it possible to build extremely accurate digital reconstructions of brain circuits. Are such unprecedented levels of biological accuracy essential for brain simulations to play the roles they are expected to play in neuroscientific research? The main goal of this paper is to clarify this question by distinguishing between various roles played by large-scale simulations in contemporary neuroscience, and by reflecting about what makes a simulation biologically accurate. It is argued that large-scale simulations may play model-oriented and prediction-oriented roles in brain research, and that the concept of biological accuracy can be interpreted as related to the plausibility of the theoretical model implemented in the simulation system, to the accuracy of the computer implementation, and to the level of details of the implemented model. Building on these observations and distinctions, it is argued that biological accuracy is not essential for a computer simulation to play the epistemic roles it is expected to play in brain research.


Asunto(s)
Encéfalo/fisiología , Simulación por Computador , Exactitud de los Datos , Neurociencias/métodos
3.
Phys Chem Chem Phys ; 22(3): 1611-1623, 2020 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-31894790

RESUMEN

Electronic circular dichroism is one of the most used spectroscopic techniques for peptide and protein structural characterization. However, while valuable experimental spectra exist for α-helix, ß-sheet and random coil secondary structures, previous studies showed important discrepancies for ß-turns, limiting their use as a reference for structural studies. In this paper, we simulated circular dichroism spectra for the best-characterized ß-turns in peptides, namely types I, II, I' and II'. In particular, by combining classical molecular dynamics simulations and state-of-the-art quantum time-dependent density functional theory (with the polarizable embedding multiscale model) computations, two common electronic circular dichroism patterns were found for couples of ß-turn types (namely, type I/type II' and type II/type I'), at first for a minimal di-peptide model (Ace-Ala-Ala-NHMe), but also for all sequences tested with non-aromatic residues in the central positions. On the other hand, as expected, aromatic substitution causes important perturbations to the previously found ECD patterns. Finally, by applying suitable approximations, these patterns were subsequently rationalized based on the exciton chirality rule. All these results provide useful predictions and pave the way for a possible experimental characterization of ß-turns based on circular dichroism spectroscopy.


Asunto(s)
Dicroismo Circular , Simulación de Dinámica Molecular , Simulación por Computador , Conformación Proteica en Lámina beta , Estructura Terciaria de Proteína
4.
J Agric Food Chem ; 68(2): 523-529, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31908169

RESUMEN

The present work sought to contribute to the development of new nematicides. Benzaldehydes were initially converted to nitrile oxides that underwent 1,3-dipolar cycloaddition reactions with methyl acrylate to generate 4,5-dihydroisoxazoles. In in vitro tests, methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (1) and methyl 3-(4-chlorophenyl)-4,5-dihydroisoxazole-5-carboxylate (4) increased the mortality of Meloidogyne exigua and Meloidogyne incognita second-stage juveniles (J2). Compounds 1 and 4 presented necessary concentrations of 398 and 501 µg mL-1, respectively, to kill 50% of M. incognita J2 (LC50 values), while the value for carbofuran (positive control) was 168 µg mL-1. In in vivo tests, compounds 1 and 4 reduced the number of M. incognita galls in tomato roots by 70 and 40%, respectively, and the number of eggs by 89 and 44%. Using an in silico approach, we showed that compounds 1 and 4 were toxic to the nematodes by binding to the allosteric binding sites of the agonist-binding domains of the nematode nicotinic acetylcholine receptors. These results opened up possibilities for further investigations aimed at developing novel commercial nematicides.


Asunto(s)
Antinematodos/toxicidad , Isoxazoles/toxicidad , Enfermedades de las Plantas/parasitología , Tylenchoidea/efectos de los fármacos , Animales , Antinematodos/química , Simulación por Computador , Proteínas del Helminto/química , Proteínas del Helminto/metabolismo , Isoxazoles/química , Lycopersicon esculentum/parasitología , Raíces de Plantas/parasitología , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Tylenchoidea/crecimiento & desarrollo , Tylenchoidea/metabolismo
5.
Nihon Yakurigaku Zasshi ; 155(1): 51-55, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-31902850

RESUMEN

A computer simulation application on pharmacokinetics, which we developed using a software, named "Stella®", has been successfully used for the virtual training of pharmacokinetics at multiple medical schools. The training course using Stella® has encouraged the medical students to optimize drug administration for individual patients on the computers. Importantly, the virtual training is free of any concern on human and animal ethics. The simulation application has been freely provided for medical schools without any restrictions and charge. For many years, it has been under constant version-upgrade in response to updates of the operating systems (OS) of personal computers or the software. Very recently, major updates of the OS and the software, and the emergence of tablet- and smartphones-type computers have been prompting us to perform a major revision of the simulation application. Here, we introduce the new version of the "web-based" simulation application that is available through any device including personal computers, tablets, and smartphones irrespective of the OSs (Microsoft Windows and Macintosh, Android, and iOS), without any extra charge unless the modification is required. We believe that the new-version of web-based simulation application will be useful not only for medical, nursing and pharmacy students, but also for medical workers who need to simulate drug pharmacokinetics on the computers before they administer drugs to the patients.


Asunto(s)
Simulación por Computador , Programas Informáticos , Estudiantes de Medicina , Animales , Humanos , Internet , Microcomputadores
6.
Top Curr Chem (Cham) ; 378(1): 14, 2020 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-31933069

RESUMEN

Classical molecular simulations can provide significant insights into the gas adsorption mechanisms and binding sites in various metal-organic frameworks (MOFs). These simulations involve assessing the interactions between the MOF and an adsorbate molecule by calculating the potential energy of the MOF-adsorbate system using a functional form that generally includes nonbonded interaction terms, such as the repulsion/dispersion and permanent electrostatic energies. Grand canonical Monte Carlo (GCMC) is the most widely used classical method that is carried out to simulate gas adsorption and separation in MOFs and identify the favorable adsorbate binding sites. In this review, we provide an overview of the GCMC methods that are normally utilized to perform these simulations. We also describe how a typical force field is developed for the MOF, which is required to compute the classical potential energy of the system. Furthermore, we highlight some of the common analysis techniques that have been used to determine the locations of the preferential binding sites in these materials. We also review some of the early classical molecular simulation studies that have contributed to our working understanding of the gas adsorption mechanisms in MOFs. Finally, we show that the implementation of classical polarization for simulations in MOFs can be necessary for the accurate modeling of an adsorbate in these materials, particularly those that contain open-metal sites. In general, molecular simulations can provide a great complement to experimental studies by helping to rationalize the favorable MOF-adsorbate interactions and the mechanism of gas adsorption.


Asunto(s)
Gases/aislamiento & purificación , Estructuras Metalorgánicas/química , Adsorción , Dióxido de Carbono/aislamiento & purificación , Simulación por Computador , Hidrógeno/aislamiento & purificación , Modelos Químicos , Modelos Moleculares , Método de Montecarlo , Electricidad Estática , Termodinámica
7.
Adv Exp Med Biol ; 1232: 299-306, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893424

RESUMEN

Hypoxic ischemic encephalopathy (HIE) is a significant cause of death and neurological disability in newborns. Therapeutic hypothermia at 33.5 °C is one of the most common treatments in HIE and generally improves outcome; however 45-55% of injuries still result in death or severe neurodevelopmental disability. We have developed a systems biology model of cerebral oxygen transport and metabolism to model the impact of hypothermia on the piglet brain (the neonatal preclinical animal model) tissue physiology. This computational model is an extension of the BrainSignals model of the adult brain. The model predicts that during hypothermia there is a 5.1% decrease in cerebral metabolism, 1.1% decrease in blood flow and 2.3% increase in cerebral tissue oxygenation saturation. The model can be used to simulate effects of hypothermia on the brain and to help interpret bedside recordings.


Asunto(s)
Circulación Cerebrovascular , Cerebro , Hipotermia , Modelos Biológicos , Animales , Animales Recién Nacidos , Circulación Cerebrovascular/fisiología , Cerebro/metabolismo , Simulación por Computador , Humanos , Hipotermia Inducida , Hipoxia-Isquemia Encefálica , Porcinos
8.
Adv Exp Med Biol ; 1232: 307-313, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31893425

RESUMEN

Near infrared optical tomography (NIROT) is a non-invasive imaging technique to provide physiological information e.g. the oxygenation of tissue. For image reconstruction in clinical and preclinical scenarios, models to accurately describe light propagation are needed. This work aims to assess the accuracy and efficiency of different models, which paves the way for an optimal design of model-based image reconstruction algorithms in NIROT for realistic tissue geometries and heterogeneities. Two popular simulators were evaluated: the Monte Carlo (MC) method based MCX and the finite element method (FEM) based Toast++. We compared simulated results with experimental data measured on a homogeneous silicone phantom with well-calibrated parameters. The laser light was focused on the center of the phantom surface and images were captured by a CCD camera in both reflection and transmission modes. For transmittance measurements, the two models showed good agreement. Both achieve a cosine similarity of ~99%. In contrast, for reflectance measurements, FEM results deviated more from the measured values than MC, yielding similarity values of 86% and 94%, respectively. This study recommends the use of MC for NIROT in reflection mode and both MC and FEM yield excellent results for transmission mode.


Asunto(s)
Análisis de Elementos Finitos , Modelos Teóricos , Método de Montecarlo , Tomografía Óptica , Algoritmos , Simulación por Computador , Análisis de Elementos Finitos/normas , Luz , Fantasmas de Imagen
9.
J Chem Theory Comput ; 16(2): 1333-1348, 2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-31917926

RESUMEN

Hydrogen/deuterium exchange (HDX) is a powerful technique to investigate protein conformational dynamics at amino acid resolution. Because HDX provides a measurement of solvent exposure of backbone hydrogens, ensemble-averaged over potentially slow kinetic processes, it has been challenging to use HDX protection factors to refine structural ensembles obtained from molecular dynamics simulations. This entails dual challenges: (1) identifying structural observables that best correlate with backbone amide protection from exchange and (2) restraining these observables in molecular simulations to model ensembles consistent with experimental measurements. Here, we make significant progress on both fronts. First, we describe an improved predictor of HDX protection factors from structural observables in simulated ensembles, parametrized from ultralong molecular dynamics simulation trajectory data, with a Bayesian inference approach used to retain the full posterior distribution of model parameters. We next present a new method for obtaining simulated ensembles in agreement with experimental HDX protection factors, in which molecular simulations are performed at various temperatures and restraint biases and used to construct multiensemble Markov State Models (MSMs). Finally, the BICePs (Bayesian Inference of Conformational Populations) algorithm is then used with our HDX protection factor predictor to infer which thermodynamic ensemble agrees best with the experiment and estimate populations of each conformational state in the MSM. To illustrate the approach, we use a combination of HDX protection factor restraints and chemical shift restraints to model the conformational ensemble of apomyoglobin at pH 6. The resulting ensemble agrees well with the experiment and gives insight into the all-atom structure of disordered helices F and H in the absence of heme.


Asunto(s)
Apoproteínas/química , Simulación por Computador , Mioglobina/química , Teorema de Bayes , Hidrógeno , Cadenas de Markov , Modelos Químicos , Modelos Moleculares , Conformación Proteica
10.
J Chem Theory Comput ; 16(2): 1359-1366, 2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-31935088

RESUMEN

Protein backbone torsion angles (Phi and Psi) are crucial for protein local conformation description. In this paper, we propose a general postprocessing method for all prediction methods, namely, OPUS-Refine, which may contribute to the field in a different way. OPUS-Refine is a sampling-based method, therefore, the results of other prediction methods can be used as its constraints. After OPUS-Refine refinement, for instance, the accuracy of Phi/Psi predicted by SPIDER3 and SPOT-1D are both increased. In addition, to facilitate the sampling efficiency, we construct a neighbor-dependent statistical torsion angles sampling database, namely, OPUS-TA, which may be useful for other sampling-based methods. Furthermore, we also introduce the contact map predicted by RaptorX to OPUS-Refine as a global structural constraint. After refinement, compared to the predicted structures obtained from RaptorX online server, the accuracy of both global structural configurations (measured by TM-score and RMSD) and local structural configurations (measured by Phi/Psi) results are improved. OPUS-Refine is a highly efficient framework, it takes only about 4 s to refine the torsion angles and 30 s to refine the global structure of a protein with 100 residues in length on a typical desktop personal computer. Therefore, the sampling-based feature and the efficiency of OPUS-Refine offer greater potentiality for it to take advantage of any other method to achieve better performance.


Asunto(s)
Simulación por Computador , Bases de Datos de Compuestos Químicos , Modelos Químicos , Proteínas/química , Modelos Moleculares , Conformación Proteica
11.
J Chem Theory Comput ; 16(2): 1319-1332, 2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-31972079

RESUMEN

Proteins in vivo endure highly various interactions from the luxuriant surrounding macromolecular cosolutes. Confinement and macromolecular crowding are the two major effects that should be considered while comparing the results of protein dynamics from in vitro to in vivo. However, efforts have been largely focused on single domain protein folding up to now, and the quantifications of the in vivo effects in terms of confinements and crowders on modulating the structure and dynamics as well as the physical understanding of the underlying mechanisms on multidomain protein folding are still challenging. Here we developed a topology-based model to investigate folding of a multidomain Y-family DNA polymerase (DPO4) within spherical confined space and in the presence of repulsive and attractive crowders. We uncovered that the entropic component of the thermodynamic driving force led by confinements and repulsive crowders increases the stability of folded states relative to the folding intermediates and unfolded states, while the enthalpic component of the thermodynamic driving force led by attractive crowders gives rise to the opposite effects with less stability. We found that the shapes of DPO4 conformations influenced by the confinements and the crowders are quite different even when only the entropic component of the thermodynamic driving force is considered. We uncovered that under all in vivo conditions, the folding cooperativity of DPO4 decreases compared to that in bulk. We showed that the loss of folding cooperativity can promote the sequential domain-wise folding, which was widely found in cotranslational multidomain protein folding, and effectively prohibit the backtracking led by topological frustrations during multidomain protein folding processes.


Asunto(s)
ADN Polimerasa Dirigida por ADN/química , ADN Polimerasa Dirigida por ADN/metabolismo , Pliegue de Proteína , Simulación por Computador , Modelos Moleculares , Conformación Proteica , Dominios Proteicos , Termodinámica
13.
Comput Biol Chem ; 84: 107197, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31901788

RESUMEN

ATP dependent ParE enzyme is as an attractive target for the development of antibacterial agents. Atom based 3D-QSAR model AADHR.187 was developed based on the thirty eight Escherichia coli ParE inhibitors. The generated model showed statistically significant coefficient of determinations for the training (R2 = 0.985) and test (R2 = 0.86) sets. The cross-validated correlation coefficient (q2) was 0.976. The utility of the generated model was validated by the enrichment study. The model was also validated with structurally diverse external test set of ten compounds. Contour plot analysis of the generated model unveiled the chemical features necessary for the E. coli ParE enzyme inhibition. Extra-precision docking result revealed that hydrogen bonding and ionic interactions play a major role in ParE protein-ligand binding. Binding free energy was computed for the data set inhibitors to validate the binding affinity. A 30-ns molecular dynamics simulation showed high stability and effective binding of inhibitor 34 within the active site of ParE enzyme. Using the best fitted model AADHR.187, pharmacophore-based high-throughput virtual screening was performed to identify virtual hits. Based on the above studies three new molecules are proposed as E. coli ParE inhibitors with high binding affinity and favourable ADME properties.


Asunto(s)
Proteínas de Escherichia coli/antagonistas & inhibidores , Escherichia coli/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Simulación por Computador , Ligandos
14.
Plast Reconstr Surg ; 145(2): 365-374, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31985623

RESUMEN

BACKGROUND: A practical application of three-dimensional printing technology has been considered a difficult area in rhinoplasty. However, the patient-specific three-dimensionally printed rhinoplasty guide based on the simulation program the authors developed could be a solution for minimizing the gap between simulation and actual surgical results. The aims of this study were to determine how a three-dimensional rhinoplasty guide based on three-dimensional simulation would link the patient to the surgeon to investigate its effectiveness. METHODS: Fifty patients who underwent rhinoplasty between January of 2017 and February of 2018 were included in this study. The patients were consulted about the desired shape of their nose based on preoperative three-dimensional photography. The confirmed three-dimensional simulation was sent to a manufacturing company for three-dimensionally printed rhinoplasty guides. In the guide group, rhinoplasty was performed based on the three-dimensionally printed rhinoplasty guide, and in the control group, procedures were performed based on the surgeon's intuition. RESULTS: The intraclass correlation coefficient test for comparing the simulated and postoperative measurements showed higher correlation in the three-dimensional printing guide group: higher correlation 11.3 percent in nasal tip projection, 21.6 percent in dorsum height, and 9.8 percent in nasolabial angle. The postoperative result of the nasal dorsum had a statistically significant difference between the two groups (p < 0.05). CONCLUSIONS: This study demonstrated the usefulness of the three-dimensionally-printed rhinoplasty guide, which delivers the preoperative simulated image in the actual clinical practice of rhinoplasty. This approach could cause a paradigm shift in simulation-based rhinoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.


Asunto(s)
Impresión Tridimensional , Rinoplastia/métodos , Adulto , Estudios de Casos y Controles , Simulación por Computador , Técnicas Cosméticas , Femenino , Humanos , Imagen Tridimensional , Masculino , Satisfacción del Paciente , Cuidados Preoperatorios/métodos , Reoperación , Estudios Retrospectivos , Resultado del Tratamiento
15.
Forensic Sci Int ; 306: 110059, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31780351

RESUMEN

In traffic accidents, the differentiation of run-over and other injuries is crucial because questions about the origin of fatal injuries often arise. It is sometimes difficult for forensic pathologists to answer them due to the superimposition of injuries or competing, potentially fatal findings. Therefore, using morphometric three-dimensional (3D) reconstructions offers new perspectives based on an interdisciplinary evaluation of all findings and traces. The morphometric 3D reconstruction includes the allocation of patterned injuries or transferred material, the determination of the origin of injuries as well as the reconstruction of the incident. The generated 3D models of persons, clothes, vehicles, incident sites and relevant objects resulting from forensic imaging, photogrammetry, 3D structured-light and laser scanning are included, as are all detected traces and damages. Three case studies are presented to illustrate the possibilities and results of morphometric 3D reconstruction. Run-over accidents have received less attention than the topic of pedestrian, bicycle and motorbike accident analysis for which there is a large body of literature. Our goal is to add to the understanding of run-over accidents using morphometric reconstruction in order to improve their analysis in the future. The possibilities of morphometric reconstructions by means of 3D techniques in run-over accidents are wide-ranging and can provide new, unexpected and significant insights.


Asunto(s)
Accidentes de Tránsito , Simulación por Computador , Medicina Legal/métodos , Imagen Tridimensional , Peatones , Humanos , Rayos Láser , Imagen por Resonancia Magnética , Masculino , Fotogrametría , Programas Informáticos , Tomografía Computarizada por Rayos X , Heridas y Traumatismos/patología
16.
J Chem Theory Comput ; 16(1): 700-710, 2020 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-31769987

RESUMEN

Two permeation mechanisms, namely the water-chain-assisted mechanism and the dehydration mechanism, have been proposed for ions through lipid membranes. In previous studies, multiple reaction coordinates and potential of mean force calculations have been applied in studying such complex transmembrane processes of ions. To reduce the expensive computational cost, we develop two new reaction coordinates in our recent work and in this work to study the two permeation mechanisms. An intrinsically one-dimensional free energy calculation method developed in our recent work is successfully employed in these studies: First, one-dimensional umbrella samplings are performed using the two reaction coordinates. Then, bin segmentations are performed along the transition paths in multidimensional phase spaces. Finally, the weighted least-square analysis method (Welsam) is used for free energy analysis. Based on the new reaction coordinates and the one-dimensional free energy calculation method, we systematically study the two transmembrane permeation mechanisms of sodium ion and chloride ion through lipid bilayers with different thicknesses. Our results suggest that the water-chain-assisted mechanism is dominant for cations, whereas the dehydration mechanism is competitive for anions through thick membranes, which is consistent with previous experimental results.


Asunto(s)
Iones/metabolismo , Membrana Dobles de Lípidos/metabolismo , Termodinámica , Agua/metabolismo , Algoritmos , Permeabilidad de la Membrana Celular , Simulación por Computador , Transporte Iónico , Modelos Biológicos , Modelos Moleculares
17.
Forensic Sci Int ; 306: 110092, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31816484

RESUMEN

Metric assessment of human crania can provide forensic practitioners and anthropological researchers with information on an individual's sex and biogeographical ancestry. However, metric methods rely on the ability of users to remain consistent with themselves and others, with any error in the data rendering conclusions invalid. Digital anthropology is a growing sub-field where human remains are digitised using a growing range of methods and technologies. These models have the potential to boost research collaboration and public engagement. However, not all of these digitisation methods have been examined critically to explore the veracity of their use within a research environment. There has also been limited research into the application of digital anthropology to craniometric analysis. This study examined the intra- and inter- observer variation of seven participants taking physical measurements from a human cranial cast with an associated set of reference values. The same measurements were also taken from three digital models of the cranial cast which were created using digital photogrammetry and laser scanning. This data was then compared to the reference values and the physical measurements taken by the lead author. This study found that there was excellent statistical agreement between the reference values and the measurements taken from the cranial cast, both physical and digital. However, the participants still exhibited variation within a range of -18mm and +30mm from the reference values. MANOVA tests showed between-subject effects on nine measurements across the participant data, and 12 measurements between the digital models. However, there is little consistency between this study and the anthropological literature as to which measurements are most prone to between-subject effects. Despite the excellent agreement shown between the reference values and the digital models this study raises a number of methodological questions regarding inter-observer error and the varying levels of data processing present in different digitisation methods.


Asunto(s)
Cefalometría/métodos , Simulación por Computador , Imagen Tridimensional , Cráneo/anatomía & histología , Cráneo/diagnóstico por imagen , Antropología Forense , Humanos , Rayos Láser , Masculino , Variaciones Dependientes del Observador , Fotogrametría , Valores de Referencia
18.
J Chem Theory Comput ; 16(1): 794-799, 2020 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-31809048

RESUMEN

Ion permeation, selectivity, and the behavior of the K+ channel selectivity filter have been studied intensively in the previous two decades. The agreement among multiple approaches used to study ion flux in K+ channels suggests a consensus mechanism of ion permeation across the selectivity that has been put to the test in recent years with the proposal of an alternative way by which ions can cross the selectivity filter of K+ channels via direct Coulomb repulsion between contacting cations. Past experimental work by Zhou and MacKinnon (J. Mol. Biol. 2004, 338, 839) showed that mutation of the site S4 reduces the total occupancy of the selectivity filter to less than two ions on average by lowering the occupancy of the S2-S4 configuration without changing the S1-S3 configuration much, and this reduction of occupancy means that ion configurations different from the ones involved in the canonical mechanism are likely to be involved. At that time, calculations using complicated kinetic networks to relate occupancy to conduction did not provide deeper insight into the conduction mechanism. Here, to help solve this enigma, umbrella sampling simulations have been performed to evaluate the potential of mean force of two KcsA mutant channels where the S4 site is substituted. Our new results provide insights into the significance of threonine in this position, revealing the effect of substitution on the alternate mechanisms of conduction proposed, involving either water or vacant sites.


Asunto(s)
Proteínas Bacterianas/metabolismo , Canales de Potasio/metabolismo , Potasio/metabolismo , Streptomyces coelicolor/metabolismo , Proteínas Bacterianas/química , Sitios de Unión , Cationes Monovalentes/metabolismo , Simulación por Computador , Cinética , Modelos Moleculares , Canales de Potasio/química , Conformación Proteica , Streptomyces coelicolor/química
19.
J Sci Food Agric ; 100(3): 986-994, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31650545

RESUMEN

BACKGROUND: Controlling the blood glucose level is an effective method to reduce type 2 diabetes and prevent diabetes-related complications. Ursolic acid is a plant extract that can reduce postprandial hyperglycemia effectively. This study aimed to explore the inhibitory effect and interaction mechanism of ursolic acid against α-amylase and α-glucosidase. RESULTS: In this study, the effect of ursolic acid on glycosidase was studied in vitro, in vivo, and in silico. The half-maximal inhibitory concentration (IC50 ) of ursolic acid on α-amylase and α-glucosidase was 0.482 ± 0.12 mg mL-1 and 0.213 ± 0.042 mg mL-1 , respectively. The results of enzymatic kinetics showed that ursolic acid inhibited α-amylase and α-glucosidase activity in a non-competitive manner. The fluorescence spectrum showed that the combination of ursolic acid and glycosidase caused the intrinsic fluorescence quenching of glycosidase. The observation of starch granules revealed that the activity of α-amylase was inhibited and the hydrolysis of starch granules was prevented in the presence of ursolic acid. Molecular docking results showed that ursolic acid bound to the inactive site of α-amylase and α-glucosidase through the formation of ursolic acid-glucosidase complex. Ursolic acid interacted with α-amylase and α-glucosidase mainly through hydrogen bonding. The postprandial hypoglycemic effect of ursolic acid in C57BL/6J mice showed that the high concentration of ursolic acid could quickly reduce postprandial blood glucose level. CONCLUSION: Ursolic acid can be considered as a natural ingredient in functional foods to control postprandial blood glucose levels and prevent diabetes by delaying the digestion of starch in foods. © 2019 Society of Chemical Industry.


Asunto(s)
Diabetes Mellitus Tipo 2/enzimología , Inhibidores Enzimáticos/química , Glicósido Hidrolasas/antagonistas & inhibidores , Hipoglucemiantes/química , Triterpenos/química , Animales , Glucemia/metabolismo , Simulación por Computador , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Glicósido Hidrolasas/química , Glicósido Hidrolasas/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Cinética , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Periodo Posprandial/efectos de los fármacos , Triterpenos/administración & dosificación
20.
Toxicol Lett ; 319: 31-39, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31707105

RESUMEN

The bioabsorption and biotoxicity of cadmium are closely related to its binding form. Currently, total concentration is used as the indicator for evaluating cadmium toxicity in food, but it might not accurately reflect cadmium's toxic effects. This study attempted to evaluate the toxicity of the different forms of cadmium including cadmium-malate, cadmium-glutathione, and cadmium-metallothionein that are commonly found in food. The in vitro physiologically based extraction test (PBET) combined with Visual MINTEQ modeling was used to predict the toxicity of different forms of cadmium, and acute toxicity testing was performed in mice for validating their results. The in vivo experimental results showed that different forms of cadmium had diverse biotoxicities of which PBET was a good predictor. In particular, the simulation of cadmium ions in PBET using the MINTEQ software revealed that the free cadmium ion content in the simulated intestinal fluid had a superior linear relationship than the total cadmium concentration with the toxicology indexes. Verification using the other two forms of cadmium confirmed the accuracy of the prediction of their biotoxicity. These findings hopefully provide an important reference for a more accurate and rapid safety assessment of cadmium in food.


Asunto(s)
Compuestos de Cadmio/farmacocinética , Compuestos de Cadmio/toxicidad , Análisis de los Alimentos , Animales , Disponibilidad Biológica , Cadmio/análisis , Simulación por Computador , Heces/química , Contaminación de Alimentos , Absorción Intestinal , Masculino , Ratones , Ratones Endogámicos ICR , Valor Predictivo de las Pruebas , Programas Informáticos , Distribución Tisular
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