Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.214
Filtrar
1.
Phys Chem Chem Phys ; 22(4): 2262-2275, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31917380

RESUMO

Recently, fatty acid binding proteins 5 and 7 (FABP5 and FABP7) have been regarded as the prospective targets for clinically treating multiple diseases related to FABPs. In this work, multiple short molecular dynamics (MSMD) simulations followed by binding free energy calculations were performed to investigate the binding selectivity of three inhibitors, namely, 65X, 8KS, and 5M8 toward FABP5 and FABP7. The RMSF analysis suggests that the structural flexibility of FABP5 is stronger than that of FABP7; moreover, the calculated molecular surface area of FABP5 is also larger than that of FABP7. Meanwhile, the results from the cross-correlation analysis show that the inhibitor bindings exert different impacts on the internal dynamics of FABP5 and FABP7. Binding free energies predicted by the molecular mechanics/generalized Born surface area (MM-GBSA) method indicate that the increase in the enthalpy changes caused by the bindings of inhibitors toward FABP7 relative to FABP5 mostly drives the binding selectivity of the inhibitors toward FABP5 versus FABP7. Hierarchical clustering analysis based on the energy contributions of separate residues and calculations of residue-based free energy decompositions were carried out by using the equilibrated MSMD trajectories. The obtained results not only recognize the hot interaction spots of inhibitors with FABP5 and FABP7, but also display that several common residues, namely, (T56, T54), (L60, F58), (E75, E73), (A76, A78), (D79, D77), (R81, R79), (R107, R109), (C120, L118), and (R129, R127) belonging to (FABP5, FABP7) induce obvious binding differences in the inhibitors toward FABP5 and FABP7. Therefore, these residues play significant roles in the binding selectivities of inhibitors toward FABP5 and FABP7.


Assuntos
Proteína 7 de Ligação a Ácidos Graxos/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Simulação de Dinâmica Molecular , Proteínas Supressoras de Tumor/antagonistas & inibidores , Sítios de Ligação , Análise por Conglomerados , Entropia , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Ligações de Hidrogênio , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Supressoras de Tumor/metabolismo
2.
Adv Exp Med Biol ; 1232: 11-17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893388

RESUMO

In the adult brain, it is well known that increases in local neural activity trigger changes in regional blood flow and, thus, changes in cerebral energy metabolism. This regulation mechanism is called neurovascular coupling (NVC). It is not yet clear to what extent this mechanism is present in the premature brain. In this study, we explore the use of transfer entropy (TE) in order to compute the nonlinear coupling between changes in brain function, assessed by means of EEG, and changes in brain oxygenation, assessed by means of near-infrared spectroscopy (NIRS). In a previous study, we measured the coupling between both variables using a linear model to compute TE. The results indicated that changes in brain oxygenation were likely to precede changes in EEG activity. However, using a nonlinear and nonparametric approach to compute TE, the results indicate an opposite directionality of this coupling. The source of the different results provided by the linear and nonlinear TE is unclear and needs further research. In this study, we present the results from a cohort of 21 premature neonates. Results indicate that TE values computed using the nonlinear approach are able to discriminate between neonates with brain abnormalities and healthy neonates, indicating a less functional NVC in neonates with brain abnormalities.


Assuntos
Encéfalo , Acoplamento Neurovascular , Espectroscopia de Luz Próxima ao Infravermelho , Adulto , Encéfalo/fisiopatologia , Encefalopatias/diagnóstico , Encefalopatias/fisiopatologia , Eletroencefalografia , Entropia , Humanos , Recém-Nascido , Acoplamento Neurovascular/fisiologia
3.
J Chem Theory Comput ; 16(1): 108-118, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31822062

RESUMO

For a first-principles understanding of macromolecular processes, a quantitative understanding of the underlying free energy landscape and in particular its entropy contribution is crucial. The stability of biomolecules, such as proteins, is governed by the hydrophobic effect, which arises from competing enthalpic and entropic contributions to the free energy of the solvent shell. While the statistical mechanics of liquids, as well as molecular dynamics simulations, have provided much insight, solvation shell entropies remain notoriously difficult to calculate, especially when spatial resolution is required. Here, we present a method that allows for the computation of spatially resolved rotational solvent entropies via a nonparametric k-nearest-neighbor density estimator. We validated our method using analytic test distributions and applied it to atomistic simulations of a water box. With an accuracy of better than 9.6%, the obtained spatial resolution should shed new light on the hydrophobic effect and the thermodynamics of solvation in general.


Assuntos
Entropia , Solventes/química , Água/química , Interações Hidrofóbicas e Hidrofílicas , Modelos Químicos , Simulação de Dinâmica Molecular , Termodinâmica
4.
J Chem Theory Comput ; 16(1): 773-781, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31756104

RESUMO

Intrinsically disordered proteins (IDPs) constitute a significant fraction of eukaryotic proteomes. High-resolution characterization of IDP conformational ensembles can help elucidate their roles in a wide range of biological processes but remains challenging both experimentally and computationally. Here, we present a generic algorithm to improve the accuracy of coarse-grained IDP models using a diverse set of experimental measurements. It combines maximum entropy optimization and least-squares regression to systematically adjust model parameters and improve the agreement between simulation and experiment. We successfully applied the algorithm to derive a transferable force field, which we term the maximum entropy optimized force field (MOFF), for de novo prediction of IDP structures. Statistical analysis of force field parameters reveals features of amino acid interactions not captured by potentials designed to work well for folded proteins. We anticipate its combination of efficiency and accuracy will make MOFF useful for studying the phase separation of IDPs, which drives the formation of various biological compartments.


Assuntos
Entropia , Proteínas Intrinsicamente Desordenadas/química , Algoritmos , Animais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Transição de Fase , Conformação Proteica , Dobramento de Proteína
5.
J Chem Phys ; 151(21): 215101, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31822099

RESUMO

The fact that allostery, a nonlocal signaling between distant binding sites, can arise mainly from the entropy balance of collective thermal modes, without conformational changes, is by now well known. However, the propensity to generate negative cooperativity is still unclear. Starting from an elastic-network picture of small protein complexes, in which effector binding is modeled by locally altering interaction strengths in lieu of adding a node-spring pair, we elucidate mechanisms particularly for such negative cooperativity. The approach via a few coupled harmonic oscillators with internal elastic strengths allows us to trace individual eigenmodes, their frequencies, and their statistical weights through successive bindings. We find that the alteration of the oscillators' couplings is paramount to covering both signs of allostery. Binding-modified couplings create a rich set of eigenmodes individually for each binding state, modes inaccessible to an ensemble of noninteracting units. The associated shifts of collective-mode frequencies, nonuniform with respect to modes and binding states, result in an enhanced optimizability, reflected by a subtle phase map of allosteric behaviors.


Assuntos
Entropia , Proteínas/química , Regulação Alostérica , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas/metabolismo
6.
Environ Monit Assess ; 192(1): 1, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792605

RESUMO

This paper defines five criteria and identifies 21 indicators for the modernization level of a province or a city in modern China. It collects raw index data from 31 provinces in China, between 2007 and 2017, and introduces formula for its dimensionless processing. An improved entropy method (IEM) is proposed for the evaluation of the modernization in urban areas, based on the five criteria and 21 indicators. A practical study was implemented in Anhui province employing the said IEM. The results demonstrate that the IEM is being effective in evaluating the modernization level in urban areas.


Assuntos
Planejamento de Cidades/métodos , Entropia , Mudança Social , China , Cidades
7.
Braz J Cardiovasc Surg ; 34(5): 572-580, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31719008

RESUMO

OBJECTIVE: To characterize the behavior of cardiac autonomic modulation in individuals with different times after orthotopic heart transplantation (HTx) using symbolic dynamics analysis. METHODS: Sixty patients were evaluated after HTx. We recorded their instantaneous R-R intervals (RRi) by cardiac monitor Polar® RS800CX™ (Polar Electro Oy, Kempele, Finland) for 10 minutes. The same sequence of RRi with 256 consecutive beats was used to perform spectral analysis and symbolic dynamics analysis. We used hierarchical clustering to form groups. One-way analysis of variance (ANOVA) (with Holm-Sidak method) or one-way Kruskal-Wallis test (with Dunn´s post-hoc test) was used to analyze the difference between groups. Linear correlation analysis between variables was performed using Pearson's or Spearman's tests. P-value < 0.05 was considered statistically significant. RESULTS: The 0V% index increased, the 2UV% index and the normalized complexity index decreased with an increase of HTx postoperative time. There were a negative correlation between complexity indexes and 0V% and a positive correlation between complexity indexes and 2UV%. CONCLUSION: Symbolic dynamics indexes were able to show a specific cardiac autonomic modulation pattern for HTx recipients with different postoperative times.


Assuntos
Transplante de Coração/reabilitação , Coração/fisiopatologia , Dinâmica não Linear , Sistema Nervoso Parassimpático/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Análise de Variância , Estudos Transversais , Entropia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Valores de Referência , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo
8.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1023-1029, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640953

RESUMO

OBJECTIVE: To compare the effectiveness and sensitivity of entropy and regional homogeneity (ReHo) for identifying irritable bowel syndrome (IBS) based on functional magnetic resonance imaging (fMRI). METHODS: Voxel-based approximate entropy (ApEn) was calculated based on findings of resting fMRI of 54 patients with IBS and 54 healthy control subjects. Feature selection was performed using independent sample t-test, and support vector machine was then used to classify and identify different groups. The classification performance obtained from ApEn was compared with that from ReHo. RESULTS: Significant differences between the two groups were found in the left triangle part of inferior prefrontal gyrus, right angular gyrus of the inferior parietal lobule, left inferior temporal gyrus, left middle temporal gyrus, left lingual gyrus, bilateral middle occipital gyrus and bilateral superior occipital gyrus for ReHo (P < 0.05), and in the bilateral postcentral gyrus, right precentral gyrus, right inferior temporal gyrus, bilateral middle temporal gyrus and left superior occipital gyrus for ApEn (P < 0.05). ApEn consistently showed better performance than ReHo regardless of the variations in the number of features. The classification accuracy, specificity and sensitivity of ApEn were 93.5185%, 90.7407% and 96.2963%, respectively, as compared with 86.1111%, 85.1852% and 87.037% of ReHo. CONCLUSIONS: Entropy analysis based on fMRI can be more sensitive and effective than ReHo for identification of IBS.


Assuntos
Síndrome do Intestino Irritável/diagnóstico por imagem , Imagem por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Estudos de Casos e Controles , Entropia , Humanos
9.
Environ Monit Assess ; 191(11): 669, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650357

RESUMO

Evaluating the relationships between wildlife species and their habitats helps to predict effects of habitat change for present and future management of wild animal populations. Building ecological models are good ways to understand and manage wildlife populations and to predict various environmental scenarios. Recently, management of ungulates is becoming more important in Europe due to a high demand of hunting and their role in biodiversity. European roe deer (Capreolus capreolus) is the smallest species of cervids and has a widespread distribution in Turkey. In this study, two habitat suitability models of roe deers, living in the Black Sea Region in Turkey, were created by using a maximum entropy (MaxEnt) approach. Two wildlife development areas, which have widely different habitat types, were selected as study sites. As a result of this study, area under the curve (AUC) values were found to be above 0.80. According to the modeling results, in two different habitat types, ecological variables are quite similar in general. This study is the first study on modeling European roe deers in Turkey.


Assuntos
Ecologia/métodos , Ecossistema , Monitoramento Ambiental/métodos , Animais , Animais Selvagens , Mar Negro , Cervos , Entropia , Europa (Continente) , Modelos Teóricos , Turquia
10.
Rev Cardiovasc Med ; 20(3): 171-177, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601091

RESUMO

Automatic and accurate segmentation of intravascular optical coherence tomography imagery is of great importance in computer-aided diagnosis and in treatment of cardiovascular diseases. However, this task has not been well addressed for two reasons. First, because of the difficulty of acquisition, and the laborious labeling from personnel, optical coherence tomography image datasets are usually small. Second, optical coherence tomography images contain a variety of imaging artifacts, which hinder a clear observation of the vascular wall. In order to overcome these limitations, a new method of cardiovascular vulnerable plaque segmentation is proposed. This method constructs a novel Deep Residual U-Net to segment vulnerable plaque regions. Furthermore, in order to overcome the inaccuracy in object boundary segmentation which previous research has shown extensively, a loss function consisting of weighted cross-entropy loss and Dice coefficient is proposed to solve this problem. Thorough experiments and analysis have been carried out to verify the effectiveness and superior performance of the proposed method.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Aprendizado Profundo , Interpretação de Imagem Assistida por Computador , Placa Aterosclerótica , Tomografia de Coerência Óptica , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Entropia , Humanos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Ruptura Espontânea
11.
Nat Commun ; 10(1): 4616, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601811

RESUMO

Prominent theories of consciousness emphasise different aspects of neurobiology, such as the integration and diversity of information processing within the brain. Here, we combine graph theory and dynamic functional connectivity to compare resting-state functional MRI data from awake volunteers, propofol-anaesthetised volunteers, and patients with disorders of consciousness, in order to identify consciousness-specific patterns of brain function. We demonstrate that cortical networks are especially affected by loss of consciousness during temporal states of high integration, exhibiting reduced functional diversity and compromised informational capacity, whereas thalamo-cortical functional disconnections emerge during states of higher segregation. Spatially, posterior regions of the brain's default mode network exhibit reductions in both functional diversity and integration with the rest of the brain during unconsciousness. These results show that human consciousness relies on spatio-temporal interactions between brain integration and functional diversity, whose breakdown may represent a generalisable biomarker of loss of consciousness, with potential relevance for clinical practice.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Transtornos da Consciência/diagnóstico por imagem , Estado de Consciência , Adolescente , Adulto , Idoso , Anestésicos Intravenosos/farmacologia , Encéfalo/efeitos dos fármacos , Transtornos da Consciência/fisiopatologia , Entropia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Propofol/farmacologia , Inconsciência/diagnóstico por imagem , Inconsciência/fisiopatologia , Vigília , Adulto Jovem
12.
J Chem Theory Comput ; 15(12): 6752-6759, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31647864

RESUMO

Free energy landscapes provide insights into conformational ensembles of biomolecules. In order to analyze these landscapes and elucidate mechanisms underlying conformational changes, there is a need to extract metastable states with limited noise. This has remained a formidable task, despite a plethora of existing clustering methods. We present InfleCS, a novel method for extracting well-defined core states from free energy landscapes. The method is based on a Gaussian mixture free energy estimator and exploits the shape of the estimated density landscape. The core states that naturally arise from the clustering allow for detailed characterization of the conformational ensemble. The clustering quality is evaluated on three toy models with different properties, where the method is shown to consistently outperform other conventional and state-of-the-art clustering methods. Finally, the method is applied to a temperature enhanced molecular dynamics simulation of Ca2+-bound Calmodulin. Through the free energy landscape, we discover a pathway between a canonical and a compact state, revealing conformational changes driven by electrostatic interactions.


Assuntos
Calmodulina/química , Entropia , Simulação de Dinâmica Molecular , Análise por Conglomerados , Estrutura Molecular , Eletricidade Estática
13.
Nat Commun ; 10(1): 4354, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554788

RESUMO

For many biological applications, exploration of the massive parametric space of a mechanism-based model can impose a prohibitive computational demand. To overcome this limitation, we present a framework to improve computational efficiency by orders of magnitude. The key concept is to train a neural network using a limited number of simulations generated by a mechanistic model. This number is small enough such that the simulations can be completed in a short time frame but large enough to enable reliable training. The trained neural network can then be used to explore a much larger parametric space. We demonstrate this notion by training neural networks to predict pattern formation and stochastic gene expression. We further demonstrate that using an ensemble of neural networks enables the self-contained evaluation of the quality of each prediction. Our work can be a platform for fast parametric space screening of biological models with user defined objectives.


Assuntos
Algoritmos , Simulação por Computador , Modelos Biológicos , Entropia , Escherichia coli/genética , Escherichia coli/metabolismo , Cinética , Processos Estocásticos
14.
Dokl Biochem Biophys ; 487(1): 260-263, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31559593

RESUMO

The interaction of Kunitz-type peptide, HMIQ3c1, from the sea anemone Heteractis magnifica with several serine proteases, including inflammatory proteases, was investigated using the surface plasmon resonance approach. We showed that the recombinant analog of HMIQ3c1 forms sufficiently strong complexes with trypsin (KD = 1.07 × 10-9 М) and chymotrypsin (KD = 4.70 × 10-8 М). Analysis of thermodynamic parameters of HMIQ3c1/chymotrypsin revealed significant contribution of the entropic factor to the complex formation. The formation of specific complexes of HMIQ3c1 with the kallikrein (KD = 2.81 × 10-8 М) and neutrophil elastase (KD = 1.11 × 10-7 М) indicates its anti-inflammatory activity and makes prospects to use the peptide as a potential therapeutic agent.


Assuntos
Peptídeos/metabolismo , Anêmonas-do-Mar/química , Sequência de Aminoácidos , Animais , Entropia , Peptídeos/química , Ligação Proteica , Serina Proteases/metabolismo , Ressonância de Plasmônio de Superfície
15.
Phys Chem Chem Phys ; 21(37): 21038-21048, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31528920

RESUMO

Dramatically different properties have been observed for two types of osmolytes, i.e., trimethylamine N-oxide (TMAO) and urea, in a protein folding process. Great progress has been made in revealing the potential underlying mechanism of these two osmolyte systems. However, many problems still remain unsolved. In this paper, we propose to use the persistent homology to systematically study the osmolytes' molecular aggregation and their hydrogen-bonding network from a global topological perspective. It has been found that, for the first time, TMAO and urea show two extremely different topological behaviors, i.e., an extensive network and local clusters, respectively. In general, TMAO forms highly consistent large loop or circle structures in high concentrations. In contrast, urea is more tightly aggregated locally. Moreover, the resulting hydrogen-bonding networks also demonstrate distinguishable features. With a concentration increase, TMAO hydrogen-bonding networks vary greatly in their total number of loop structures and large-sized loop structures consistently increase. In contrast, urea hydrogen-bonding networks remain relatively stable with slight reduction of the total loop number. Moreover, the persistent entropy (PE) is, for the first time, used in characterization of the topological information of the aggregation and hydrogen-bonding networks. The average PE systematically increases with the concentration for both TMAO and urea, and decreases in their hydrogen-bonding networks. But their PE variances have totally different behaviors. Finally, topological features of the hydrogen-bonding networks are found to be highly consistent with those from the ion aggregation systems, indicating that our topological invariants can characterize intrinsic features of the "structure making" and "structure breaking" systems.


Assuntos
Metilaminas/química , Ureia/química , Entropia , Hidrogênio/química , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Agregação Patológica de Proteínas , Homologia Estrutural de Proteína
16.
Phys Chem Chem Phys ; 21(37): 20951-20964, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31524891

RESUMO

As a promising drug target in the treatment of lung cancer, anaplastic lymphoma kinase (ALK) and its mutations have been studied widely through the development of multiple generations of inhibitors. Experiments have found that compared with the wild-type, the L1198F and C1156Y/L1198F mutations resulted in resistance to 5P8 inhibitors, and the C1156Y mutation resulted in resistance to VGH inhibitors. In this study, the newly developed interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field was utilized to explore the origin of the resistance mechanism of the ALK mutant system. The calculated binding free energy was consistent with the experimental results. Per-residue binding free energy decomposition showed that the predicted hot-spot residues (LEU1122, LEU/PHE1198, MET1199, GLY1202 and LEU1256) were almost identical across systems. Especially, the GLU1197 residue played an important role in inducing drug-resistance for both inhibitors. The electrostatic interaction of GLU1197, PHE1198 and MET1199 mainly resulted in the resistances of the L1198F and C1156Y/L1198F mutations to 5P8. And the van der Waals interaction energy of LEU1256 residue, and electrostatic energy and entropy change of GLU1197 resulted in the resistances of the C1156Y mutations to VGH. The indicated origins of the drug-resistance in the ALK systems provide a theoretical foundation for the design of potent inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Entropia , Mutação/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Eletricidade Estática
17.
Phys Rev E ; 100(1-1): 012405, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31499811

RESUMO

In the analysis of signal regularity from a physiological system such as the human heart, Approximate entropy (H_{A}) and Sample entropy (H_{S}) have been the most popular statistical tools used so far. While studying heart rate dynamics, it nevertheless becomes more important to extract information about complexities associated with the heart, rather than the regularity of signal patterns produced by it. A complex physiological system does not necessarily produce irregular signals and vice versa. In order to equip a regularity statistic to see through the respective system's level of complexity, the idea of multiscaling was introduced in H_{S} estimation. Multiscaling ideally requires an input signal to be (a) long and (b) stationary. However, the longer the data is the less stationary it is. The requirement multiscaling places on its data length largely limits its accuracy. We propose a novel method of entropy profiling that makes multiscaling require very short signal segments, granting better prospects of signal stationarity and estimation accuracy. With entropy profiling, an efficient multiscale H_{S} based analysis requires only 500-beat signals of atrial fibrillated data, as opposed to the earlier case that required at least 20 000 beats.


Assuntos
Entropia , Frequência Cardíaca , Modelos Biológicos
18.
Chem Commun (Camb) ; 55(77): 11615-11618, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31501837

RESUMO

To date, implementation of renewable DNA circuits remains challenging due to issues including reactant depletion and waste accumulation. Herein we simultaneously addressed both issues through nicking enzyme-assisted waste-to-reactant transformation. As a proof-of-concept, a renewable entropy-driven catalytic DNA circuit was implemented, exhibiting a good renewability when replenishing fuel.


Assuntos
DNA Catalítico/química , Endonucleases/química , Redes Reguladoras de Genes , Pareamento Incorreto de Bases , Catálise , Entropia , Corantes Fluorescentes/química , Cinética , Conformação de Ácido Nucleico , Estudo de Prova de Conceito , Espectrometria de Fluorescência
19.
J Mol Model ; 25(10): 308, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31502063

RESUMO

In the last years, H2S has been recognized as a signaling molecule in mammals, which can synthesize and catabolize (by oxidation) such species. The latter process is accelerated by a sulfide:quinone oxidoreductase (SQR, E.C. 1.8.5.4), a flavin-dependent sulfide oxidase (FDSO). FDSOs catalyze electron transfer from H2S to an acceptor in catalytic cycles involving two phases: (I) reduction of FAD by H2S (SH-) and (II) electron transfer from FADH- to the electron acceptor. The first step of FAD reduction consists on the reaction of SH- with a catalytic disulfide at the active site of the enzyme, to yield a thiolate and a persulfide in the protein. This step is ca. 106 times faster than the analogous reaction with low-molecular-weight disulfides (LMWDs) and the causes of such extraordinary acceleration remain unknown. Using the IEF-PCM(ε ≈ 10)/M06-2X-D3/6-31+G(d,p) level of theory, we have modeled the reaction of SH- with a disulfide as located in a representative model of the active site extracted from a prokaryotic SQR, assessing the effects of partial covalent interactions (PCIs) between the leaving sulfur atom and flavin ring on the activation Gibbs free-energy barrier at 298 K (∆‡G298K). To also evaluate the importance of entropic penalties on the first step, we have modeled at the same level of theory the reaction of (bis)hydroxyethyl disulfide in aqueous solution, a LMWD for which experimental data is available. Our results show that PCIs between the leaving sulfur atom and the flavin group only have a minor effect (∆‡G298K reduced by 1.6 kcal mol-1) while compensating entropic penalties could have a much larger effect (up to 8.3 kcal mol-1). Finally, we also present here a first model of some of further steps in the phase I of the catalytic cycle as in mammalian FDSOs, providing some light about their detailed mechanism. Graphical abstract .


Assuntos
Teoria da Densidade Funcional , Flavinas/metabolismo , Sulfeto de Hidrogênio/metabolismo , Modelos Moleculares , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Acidithiobacillus/enzimologia , Biocatálise , Domínio Catalítico , Dissulfetos/metabolismo , Entropia , Oxirredução
20.
BMC Bioinformatics ; 20(1): 455, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492097

RESUMO

BACKGROUND: Evolutionary information contained in the amino acid sequences of proteins specifies the biological function and fold, but exactly what information contained in the protein sequence drives both of these processes? Considerable progress has been made to answer this fundamental question, but it remains challenging to explore the potential space of cooperative interactions between amino acids. Statistical analysis plays a significant role in studying such interactions and its use has expanded in recent years to studies ranging from coevolution-guided rational protein design to protein folding in silico. RESULTS: Here we describe a computational tool named Sibe for use in studies of protein sequence, folding, and design using evolutionary coupling between amino acids as a driving factor. In this study, Sibe is used to identify positionally conserved couplings between pairwise amino acids and aid rational protein design. In this process, pairwise couplings are filtered according to the relative entropy computed from the positional conservations and grouped into several 'blocks', which could contribute to driving protein folding and design. A human ß2-adrenergic receptor (ß2AR) was used to demonstrate that those 'blocks' contribute the rational design for specifying functional residues. Sibe also provides folding modules based on both the positionally conserved couplings and well-established statistical potentials for simulating protein folding in silico and predicting tertiary structure. Our results show that statistically inferences of basic evolutionary principles, such as conservations and coupled-mutations, can be used to rapidly design a diverse set of proteins and study protein folding. CONCLUSIONS: The developed software Sibe provides a computational tool for systematical analysis from protein primary to its tertiary structure using the evolutionary couplings as a driving factor. Sibe, written in C++, accounts for compatibility with the 'big data' era in biological science, and it primarily focuses on protein sequence analysis, but it is also applicable to extend to other modeling and predictions of experimental measurements.


Assuntos
Biologia Computacional/métodos , Simulação por Computador , Engenharia de Proteínas , Dobramento de Proteína , Proteínas/química , Proteínas/genética , Sequência de Aminoácidos , Entropia , Humanos , Mutação , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/genética , Análise de Sequência , Software
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA