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1.
Proc Natl Acad Sci U S A ; 117(25): 13967-13974, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32503918

RESUMO

Molecular dynamics and free energy simulations have been carried out to elucidate the structural origin of differential protein-protein interactions between the common receptor protein angiotensin converting enzyme 2 (ACE2) and the receptor binding domains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [A. E. Gorbalenya et al., Nat. Microbiol. 5, 536-544 (2020)] that causes coronavirus disease 2019 (COVID-19) [P. Zhou et al., Nature 579, 270-273 (2020)] and the SARS coronavirus in the 2002-2003 (SARS-CoV) [T. Kuiken et al., Lancet 362, 263-270 (2003)] outbreak. Analysis of the dynamic trajectories reveals that the binding interface consists of a primarily hydrophobic region and a delicate hydrogen-bonding network in the 2019 novel coronavirus. A key mutation from a hydrophobic residue in the SARS-CoV sequence to Lys417 in SARS-CoV-2 creates a salt bridge across the central hydrophobic contact region, which along with polar residue mutations results in greater electrostatic complementarity than that of the SARS-CoV complex. Furthermore, both electrostatic effects and enhanced hydrophobic packing due to removal of four out of five proline residues in a short 12-residue loop lead to conformation shift toward a more tilted binding groove in the complex in comparison with the SARS-CoV complex. On the other hand, hydrophobic contacts in the complex of the SARS-CoV-neutralizing antibody 80R are disrupted in the SARS-CoV-2 homology complex model, which is attributed to failure of recognition of SARS-CoV-2 by 80R.


Assuntos
Betacoronavirus/fisiologia , Peptidil Dipeptidase A/metabolismo , Ligação Proteica , Receptores Virais/metabolismo , Aminoácidos/química , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , Infecções por Coronavirus , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral , Domínios Proteicos , Eletricidade Estática
2.
Int J Food Microbiol ; 328: 108663, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32454366

RESUMO

ε-Polylysine (ε-PL) is a natural and highly effective cationic antimicrobial, of which antibacterial activity is limited in food matrix because of ε-PL's charged amino groups that form complexes with food polyanions. Whey protein-ε-PL complexes delivery system was found to be able to solve the problem and keep the antibacterial activity. This study investigated the antibacterial activity of the complexes and its mechanism against Escherichia coli. The minimal inhibitory concentration of ε-PL was in the range 11.72-25.00 g/mL for the complexes containing different amount of ε-PL and was similar to that of free ε-PL. The results of scanning electron microscopy showed that the complexes could destroy the structure of E. coli cell membrane surface, leaving holes on the surface of the bacteria, leading to the death of the bacteria. The molecular dynamics simulation results showed that the mechanism of the antibacterial activity of the complexes was as follows: under electrostatic interaction, the complexes captured the phospholipid molecules of the bacterial membrane through the hydrogen bonds between the positively charged amino groups of ε-PL and the oxygen atom of the phosphate head groups of the membrane, which could create holes on the surface of the bacteria and lead to the death of the bacteria. The results of activity on real food systems showed that the complexes kept the number of E. coli within 5.8 log10 CFU/g after 7 d storage in sauced duck products, while the positive control (ε-PL) was 6.5 log10 CFU/g and negative control (sterile water) was 7.8 log10 CFU/g. Overall, this study confirmed the antibacterial activity of the complexes and provided fundamental knowledge of its antibacterial activity mechanism.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Escherichia coli/efeitos dos fármacos , Polilisina/farmacologia , Proteínas do Soro do Leite/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Patos , Microbiologia de Alimentos , Ligação de Hidrogênio/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Proteínas do Soro do Leite/metabolismo
3.
J Phys Chem Lett ; 11(12): 4785-4790, 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32463239

RESUMO

The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic is setting the global health crisis of our time, causing a devastating societal and economic burden. An idiosyncratic trait of coronaviruses is the presence of spike glycoproteins on the viral envelope, which mediate the virus binding to specific host receptor, enabling its entry into the human cells. In spite of the high sequence identity of SARS-CoV-2 with its closely related SARS-CoV emerged in 2002, the atomic-level determinants underlining the molecular recognition of SARS-CoV-2 to the angiotensin-converting enzyme 2 (ACE2) receptor and, thus, the rapid virus spread into human body, remain unresolved. Here, multi-microsecond-long molecular dynamics simulations enabled us to unprecedentedly dissect the key molecular traits liable of the higher affinity/specificity of SARS-CoV-2 toward ACE2 as compared to SARS-CoV. This supplies a minute per-residue contact map underlining its stunningly high infectivity. Harnessing this knowledge is pivotal for urgently developing effective medical countermeasures to face the ongoing global health crisis.


Assuntos
Betacoronavirus/metabolismo , Glicoproteínas/metabolismo , Simulação de Dinâmica Molecular , Proteínas Virais/metabolismo , Motivos de Aminoácidos , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Glicoproteínas/química , Humanos , Ligação de Hidrogênio , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ligação Proteica , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Teoria Quântica , Vírus da SARS/metabolismo , Proteínas Virais/química , Ligação Viral
4.
Nature ; 581(7807): 215-220, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32225176

RESUMO

A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world1-3. Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1-3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.


Assuntos
Betacoronavirus/química , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Receptores Virais/química , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Anticorpos Neutralizantes/imunologia , Betacoronavirus/metabolismo , Sítios de Ligação , Sequência Conservada , Cristalografia por Raios X , Epitopos/química , Epitopos/imunologia , Evolução Molecular , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Ligação Proteica , Domínios Proteicos , Vírus da SARS/química , Sais/química , Alinhamento de Sequência , Água/análise , Água/química
5.
Life Sci ; 250: 117602, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32240677

RESUMO

AIMS: Extrinsic ageing or photoageing relates to the onset of age-linked phenotypes such as skin hyperpigmentation due to UV exposure. UV induced upregulated production of tyrosinase enzyme, which catalyses the vital biochemical reactions of melanin synthesis is responsible for the inception of skin hyperpigmentation. We aimed to generate a validated QSAR model with a dataset consisting of 69 thio-semicarbazone derivatives to elucidate the physicochemical properties of compounds essential for tyrosinase inhibition and to identify novel lead molecules with enhanced tyrosinase inhibitory activity and bioavailability. MAIN METHODS: Lead optimization and insilico approaches were employed in this research work. QSAR model was generated and validated by exploiting Multiple Linear Regression method. Prioritization of lead-like compounds was accomplished by performing multi parameter optimization depleting molecular docking, bioavailability assessments and toxicity prediction for 69 compounds Derivatives of best lead compound were retrieved from chemical spaces. KEY FINDINGS: Molecular descriptors explicated the significance of chemical properties essential for chelation of copper ions present in the active site of tyrosinase protein target. Further, derivatives which comprise of electron donating groups in their chemical structure were predicted and analysed for tyrosinase inhibitory activity by employing insilico methodologies including chemical space exploration. SIGNIFICANCE: Our research work resulted in the generation of a validated QSAR model with higher degree of external predictive ability and significance to tyrosinase inhibitory activity. We propose 11 novel derivative compounds with enhanced tyrosinase inhibitory activity and bioavailability.


Assuntos
Química Farmacêutica/métodos , Biologia Computacional/métodos , Indóis/antagonistas & inibidores , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pele/efeitos dos fármacos , Agaricales/metabolismo , Domínio Catalítico , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Elétrons , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Relação Quantitativa Estrutura-Atividade , Pigmentação da Pele/efeitos dos fármacos , Tiossemicarbazonas/química , Raios Ultravioleta
6.
Acta Crystallogr C Struct Chem ; 76(Pt 4): 328-345, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32229714

RESUMO

Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc-tyrosine or Fmoc-phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc-protected amino acid, namely, 2-{[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino}-3-{4-[(2-hydroxypropan-2-yl)oxy]phenyl}propanoic acid or N-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, Fmoc-N-Me-Tyr(t-Bu)-OH, C29H31NO5, was successfully synthesized and the structure of its unsolvated form was determined by single-crystal X-ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N-Fmoc-phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047-8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H...H, C...H/H...C and O...H/H...O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen-bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C-H...O, C-H...π, (fluorenyl)C-H...Cl(I), C-Br...π(fluorenyl) and C-I...π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long-Range Synthon Aufbau Modules, further supported by energy-framework calculations, are discussed. Furthermore, the relevance of Fmoc-based supramolecular hydrogen-bonding patterns in biocomplexes are emphasized, for the first time.


Assuntos
Aminoácidos/química , Fluorenos/síntese química , Metiltirosinas/química , Fenilalanina/química , Aminoácidos/síntese química , Simulação por Computador , Cristalografia por Raios X , Fluorenos/química , Ligação de Hidrogênio , Conformação Molecular , Inquéritos e Questionários
7.
Acta Crystallogr C Struct Chem ; 76(Pt 4): 359-366, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32229717

RESUMO

Derivatives of pyrimidine-2(1H)-selenone are a group of compounds with very strong antimicrobial activity. In order to study the effect of the position of the methoxy substituent on biological activity, molecular geometry and intermolecular interactions in the crystal, three derivatives were prepared and evaluated with respect to their antimicrobial activities, and their crystal structures were determined by X-ray diffraction. The investigated compounds, namely, 1-(X-methoxyphenyl)-4-methyl-6-phenylpyrimidine-2(1H)-selenones (X = 2, 3 and 4 for 1, 2 and 3, respectively), C18H16N2OSe, showed very strong activity against selected strains of Gram-positive bacteria and fungi. Two compounds, 1 and 2, crystallize in the monoclinic space group P21/c, while 3 crystallizes in the space group P21/n; 1 has two molecules in the asymmetric unit and the other two (2 and 3) have one molecule. The geometries of the investigated compounds differ slightly in the mutual orientations of the aromatic and pyrimidineselenone rings. The O atom in 1 stabilizes the conformation of the molecules via intramolecular C-H...O hydrogen bonding. The packing of molecules is determined by weak C-H...N and C-H...Se intermolecular interactions and additionally in 1 and 2 by C-H...O intermolecular interactions. The introduction of the methoxy substituent results in greater selectivity of the investigated compounds.


Assuntos
Anti-Infecciosos/química , Pirimidinas/química , Anti-Infecciosos/farmacologia , Cristalografia por Raios X , Fungos , Ligação de Hidrogênio , Estrutura Molecular
8.
Life Sci ; 251: 117627, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251634

RESUMO

AIMS: In December 2019, the Coronavirus disease-2019 (COVID-19) virus has emerged in Wuhan, China. In this research, the first resolved COVID-19 crystal structure (main protease) was targeted in a virtual screening study by of FDA approved drugs dataset. In addition, a knowledge gap in relations of COVID-19 with the previously known fatal Coronaviruses (CoVs) epidemics, SARS and MERS CoVs, was covered by investigation of sequence statistics and phylogenetics. MATERIALS AND METHODS: Molecular modeling, virtual screening, docking, sequence comparison statistics and phylogenetics of the COVID-19 main protease were investigated. KEY FINDINGS: COVID-19 Mpro formed a phylogenetic group with SARS CoV that was distant from MERS CoV. The identity% was 96.061 and 51.61 for COVID-19/SARS and COVID-19/MERS CoV sequence comparisons, respectively. The top 20 drugs in the virtual screening studies comprised a broad-spectrum antiviral (ribavirin), anti-hepatitis B virus (telbivudine), two vitamins (vitamin B12 and nicotinamide) and other miscellaneous systemically acting drugs. Of special interest, ribavirin had been used in treating cases of SARS CoV. SIGNIFICANCE: The present study provided a comprehensive targeting of the first resolved COVID+19 structure of Mpro and found a suitable save drugs for repurposing against the viral Mpro. Ribavirin, telbivudine, vitamin B12 and nicotinamide can be combined and used for COVID treatment. This initiative relocates already marketed and approved safe drugs for potential use in COVID-treatment.


Assuntos
Antivirais/química , Betacoronavirus/enzimologia , Cisteína Endopeptidases/química , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Proteínas não Estruturais Virais/química , Sequência de Aminoácidos , Antivirais/farmacologia , Sítios de Ligação , Curcumina/química , Curcumina/farmacologia , Aprovação de Drogas , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Coronavírus da Síndrome Respiratória do Oriente Médio/enzimologia , Modelos Moleculares , Inibidores de Proteases/farmacologia , Vírus da SARS/enzimologia , Alinhamento de Sequência , Estados Unidos , United States Food and Drug Administration
9.
Acta Crystallogr C Struct Chem ; 76(Pt 3): 269-275, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32132285

RESUMO

A new iridoid glycoside, methyl (3R,4R,4aS,7S,7aR)-3-hydroxy-7-methyl-5-oxooctahydrocyclopenta[c]pyran-4-carboxylate-3-O-ß-D-(1'S,2'R,3'S,4'S,5'R)-glucopyranoside, named loniceroside A, C17H26O10, (1), was obtained from the aerial parts of Lonicera saccata. Its structure was established based on an analysis of spectroscopic data, including 1D NMR, 2D NMR and HRESIMS, and the configurations of the chiral C atoms were determined by X-ray crystallographic analysis. The single-crystal structure reveals that the cyclopenta[c]pyran scaffold is formed from a five-membered ring and a chair-like six-membered ring connected through two bridgehead chiral C atoms. In the solid state, the glucose group of (1) plays an important role in constructing an unusual supramolecular motif. The structure analysis revealed adjacent molecules linked together through intermolecular O-H...O hydrogen bonds to generate a banded structure. Furthermore, the banded structures are linked into a three-dimensional network by interesting hydrogen bonds. Biogenetically, compound (1) carries a glucopyranosyloxy moiety at the C-3 position, representing a rare structural feature for naturally occurring iridoid glycosides. The growth inhibitory effects against human cervical carcinoma cells (Hela), human lung adenocarcinoma cells (A549), human acute mononuclear granulocyte leukaemia (THP-1) and the human liver hepatocellular carcinoma cell line (HepG2) were evaluated by the MTT method.


Assuntos
Citotoxinas/farmacologia , Glicosídeos Iridoides/farmacologia , Lonicera/química , Cristalografia por Raios X , Citotoxinas/isolamento & purificação , Humanos , Ligação de Hidrogênio , Glicosídeos Iridoides/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular
10.
Phys Chem Chem Phys ; 22(13): 6919-6927, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32181454

RESUMO

The amino acid lysine has been shown to prevent water crystallization at low temperatures in saturated aqueous solutions [S. Cerveny and J. Swenson, Phys. Chem. Chem. Phys., 2014, 16, 22382-22390]. Here, we investigate two ratios of water and lysine (5.4 water molecules per lysine (saturated) and 11 water molecules per lysine) by means of the complementary use of computer simulations and neutron diffraction. By performing a detailed structural analysis we have been able to explain the anti-freeze properties of lysine by the strong hydrogen bond interactions of interstitial water molecules with lysine that prevent them from forming crystalline seeds. Additional water molecules beyond the 1 : 5.4 proportion are no longer tightly bonded to lysine and therefore are free to form crystals.


Assuntos
Simulação por Computador , Crioprotetores/química , Lisina/química , Modelos Moleculares , Difração de Nêutrons , Água/química , Cristalização , Ligação de Hidrogênio , Soluções/química
11.
Chemosphere ; 252: 126292, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32203779

RESUMO

New particle formation (NPF) involving amines in the atmosphere is considered an aggregation process, during which stable molecular clusters are formed from amines and sulfuric acid via hydrogen bond interaction. In this work, ab initio dynamics simulations of ammonium bisulfate formation from a series of amines, SO3, and H2O molecules were carried out in the gas phase and at the air-water interface. The results show that reactions between amines and hydrated SO3 molecules in the gas phase are barrierless or nearly barrierless processes. The reaction rate is related to the basicity of gas-phase amines-the stronger the basicity, the faster the reaction. Furthermore, SO3 hydrolysis catalyzed by amines occurs simultaneously with H2SO4-amine cluster formation. At the air-water interface, reactions between amines and SO3 involve multiple water molecules. The reaction center's ring structure (amine-SO3-nH2O) promotes the transfer of protons in the water molecules. The formed ammonium cation (-RNH3+) and the bisulfate anion (HSO4-) are present and stable by means of hydrogen bond interaction. The cluster formation mechanism provides new insights into NPF involving amines, which may play an important role in the formation of aerosols in some heavily polluted areas - e.g., those with a high amine concentration.


Assuntos
Aminas/química , Modelos Químicos , Sulfitos/química , Aerossóis , Atmosfera/química , Catálise , Ligação de Hidrogênio , Hidrólise , Prótons , Ácidos Sulfúricos , Água/química
12.
Chemosphere ; 251: 126395, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32155498

RESUMO

Deoxynucleotides can be good monomers for arsenite ion-imprinted polymers (IIPs) due to the successful obtainment of aptamers which can specifically recognize arsenite. However, the recognition and interaction mechanism between arsenite and deoxynucleotides is still not clear. In this work, the binding interactions between arsenite and deoxynucleotides (dAMP, dTMP, dGMP, dCMP) as pH changing from 1 to 14 were investigated using density functional theory calculations as well as spectroscopy analysis. dGMP was calculated to have the largest affinity towards arsenite. H3AsO30-dGMP0 binding at phosphate group, H3AsO30-dAMP2-, H3AsO30-dCMP0 and H3AsO30-dTMP2- binding around nucleobase were found to be the most stable complexes. This suggests the optimal pH ranges for binding interactions of dAMP, dCMP, dGMP and dTMP towards arsenite might be 6.10-9.23, 1.00-4.50, 1.00-2.40 and 6.40-9.23, respectively, which agree with UV/VIS experimental results. Reduced Density Gradient method indicated that the binding interactions of arsenite with deoxynucleotides are mainly attributed to hydrogen bonds (H-bond). The strengths of these H-bonds are affected by pH. FT-IR and NMR spectroscopy analysis also provided essential H-bonding information, giving direct evidence to support the computational conclusions.


Assuntos
Arsenitos/química , Modelos Químicos , Nucleotídeos de Desoxiguanina , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Substâncias Macromoleculares/química , Espectroscopia de Infravermelho com Transformada de Fourier
13.
Chemosphere ; 251: 126345, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32169696

RESUMO

This study aimed at investigating whether stable isotopes can be used to monitor the progress of volatile organic compounds (VOCs) volatilization from contaminated sediment during venting. Batches of a dry aquifer sediment were packed into stainless steel HPLC columns, humidified with distilled water and later contaminated by either liquid toluene or propan-2-ol. The VOCs were then volatilized by a stream of gas at room temperature, and the concentrations and stable isotope ratios of gaseous VOCs were recorded by isotope-ratio mass spectrometry. During early stages of volatilization of toluene, the isotope ratios Δδ13C shifted to more negative values by about -3 to -5‰ and the Δδ2H by more than -40‰, while the concentration remained at or near initial saturated vapor concentration. Depletion of the isotope ratios in the gas was explained by the vapor-liquid fractionation process, which is amplified by successive self-partitioning steps of gaseous VOC into remaining liquid VOC. For propan-2-ol the carbon isotope shift was negative like for toluene, whereas the H shift was positive. Hydrogen bonding in the liquid propan-2-ol phase causes a normal vapor-liquid H isotope effect which was described already in classical literature. The isotope shifts in the present experiments are larger than previously reported shifts due to phase-change processes and reach the magnitude of shifts usually observed in kinetic isotope fractionation.


Assuntos
2-Propanol/química , Água Subterrânea/química , Tolueno/química , Carbono , Isótopos de Carbono/análise , Fracionamento Químico/métodos , Gases/análise , Hidrogênio/análise , Ligação de Hidrogênio , Areia , Tolueno/análise , Compostos Orgânicos Voláteis/análise , Volatilização
14.
Chemosphere ; 249: 126554, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32213394

RESUMO

Polybrominated diphenyl ethers (PBDEs) are more frequently suspected with the induction of toxicity via signal transduction pathway of cytosolic aryl hydrocarbon receptor (AhR), the initial binding to which is assumed to be an essential prerequisite during the ligand-dependent activation. However, the AhR binding property and associated toxicity of PBDEs is yet to be clearly known for lacking insights into the structural requirements at molecular level. To understand the AhR binding property of PBDEs, the ligand binding domain (LBD) of AhR was simulatively developed on homologous protein after basic validation of geometrical rationality and the binding interaction profile was visually described using molecular docking approach. For AhR binding, the offset or edge-on π-π stackings with aromatic motifs including Phe289, Phe345 and His285 were shown to be structurally required whereas the electrostatic attraction validated for AhR binding to dioxins might be less effective for 2,2',3,4,4'-pentabromodiphenyl ether (BDE-85). Besides the demands of less steric hindrance from alanines and weak formulation of hydrogen bonds, the dispersion force through large contact and polarization of S-π electrons seemed to be impactful when BDE-85 were closer to Cys327, Met334 or Met342. With theoretical computation of AhR binding energies, the more significant correlativity with bioassays was derived especially for the lowly/moderately brominated congeners, and could be used to predict the AhR binding affinity on certain degree. The informative results would thus not only help well understand the molecular basis of AhR-mediated toxicity but give an approach for accelerative evaluation of AhR binding and toxicity of PBDEs.


Assuntos
Poluentes Ambientais/toxicidade , Éteres Difenil Halogenados/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Bioensaio , Éteres Difenil Halogenados/metabolismo , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Bifenil Polibromatos/farmacologia , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos
15.
J Med Virol ; 92(6): 693-697, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32167173

RESUMO

An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an important polymerase that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (-9.11 kcal/mol), SARS-CoV (-8.03 kcal/mol), and MERS-CoV (-8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of -8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Biflavonoides/química , Catequina/química , Medicamentos de Ervas Chinesas/química , RNA Replicase/química , Proteínas Virais/química , Sequência de Aminoácidos , Antivirais/farmacologia , Betacoronavirus/enzimologia , Betacoronavirus/genética , Biflavonoides/farmacologia , Domínio Catalítico , Catequina/farmacologia , Biologia Computacional/métodos , Medicamentos de Ervas Chinesas/farmacologia , Expressão Gênica , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/enzimologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Simulação de Acoplamento Molecular , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , RNA Replicase/antagonistas & inibidores , RNA Replicase/genética , RNA Replicase/metabolismo , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/enzimologia , Vírus da SARS/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Termodinâmica , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética , Proteínas Virais/metabolismo
16.
PLoS One ; 15(3): e0230780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214349

RESUMO

Calprotectin is a heterodimeric protein complex with two subunits called S100A8/A9. The protein has an essential role in inflammation process and various human diseases. It has the ability to bind to unsaturated fatty acids including Arachidonic acid, Oleic acid and etc., which could be considered as a major carrier for fatty acids. In this study we aimed to appraise the thermodynamics and structural changes of Calprotectin in presence of Arachidonic acid/Oleic acid) using docking and molecular dynami simulation method. To create the best conformation of Calprotectin-Oleic acid/Arachidonic acid complexes, the docking process was performed. The complexes with the best binding energy were selected as the models for molecular dynamics simulation process. Furthermore, the structural and thermodynamics properties of the complexes were evaluated too. The Root Mean Square Deviation and Root Mean Square Fluctuation results showed that the binding of Arachidonic acid/Oleic acid to Calprotectin can cause the protein structural changes which was confirmed by Define Secondary Structure of Proteins results. Accordingly, the binding free energy results verified that binding of Oleic acid to Calprotectin leads to instability of S100A8/A9 subunits in the protein. Moreover, the electrostatic energy contribution of the complexes (Calprotectin-Oleic acid/Arachidonic acid) was remarkably higher than van der Waals energy. Thus, the outcome of this study confirm that Oleic acid has a stronger interaction with Calprotectin in comparison with Arachidonic acid. Our findings indicated that binding of unsaturated fatty acids to Calprotectin leads to structural changes of the S100A8/A9 subunits which could be beneficial to play a biological role in inflammation process.


Assuntos
Ácido Araquidônico/farmacologia , Complexo Antígeno L1 Leucocitário/química , Complexo Antígeno L1 Leucocitário/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ácidos Oleicos/farmacologia , Ácido Araquidônico/metabolismo , Ligação de Hidrogênio , Ácidos Oleicos/metabolismo , Conformação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos
17.
BMC Bioinformatics ; 21(Suppl 2): 85, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32164553

RESUMO

BACKGROUND: In the field of protein engineering and biotechnology, the discovery and characterization of structural patterns is highly relevant as these patterns can give fundamental insights into protein-ligand interaction and protein function. This paper presents GSP4PDB, a bioinformatics web tool that enables the user to visualize, search and explore protein-ligand structural patterns within the entire Protein Data Bank. RESULTS: We introduce the notion of graph-based structural pattern (GSP) as an abstract model for representing protein-ligand interactions. A GSP is a graph where the nodes represent entities of the protein-ligand complex (amino acids and ligands) and the edges represent structural relationships (e.g. distances ligand - amino acid). The novel feature of GSP4PDB is a simple and intuitive graphical interface where the user can "draw" a GSP and execute its search in a relational database containing the structural data of each PDB entry. The results of the search are displayed using the same graph-based representation of the pattern. The user can further explore and analyse the results using a wide range of filters, or download their related information for external post-processing and analysis. CONCLUSIONS: GSP4PDB is a user-friendly and efficient application to search and discover new patterns of protein-ligand interaction.


Assuntos
Ligantes , Proteínas/metabolismo , Interface Usuário-Computador , Animais , Bases de Dados de Proteínas , Humanos , Ligação de Hidrogênio , Mapas de Interação de Proteínas , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas/química , Dedos de Zinco
18.
BMC Bioinformatics ; 21(Suppl 2): 80, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32164574

RESUMO

BACKGROUND: Interactions between proteins and non-proteic small molecule ligands play important roles in the biological processes of living systems. Thus, the development of computational methods to support our understanding of the ligand-receptor recognition process is of fundamental importance since these methods are a major step towards ligand prediction, target identification, lead discovery, and more. This article presents visGReMLIN, a web server that couples a graph mining-based strategy to detect motifs at the protein-ligand interface with an interactive platform to visually explore and interpret these motifs in the context of protein-ligand interfaces. RESULTS: To illustrate the potential of visGReMLIN, we conducted two cases in which our strategy was compared with previous experimentally and computationally determined results. visGReMLIN allowed us to detect patterns previously documented in the literature in a totally visual manner. In addition, we found some motifs that we believe are relevant to protein-ligand interactions in the analyzed datasets. CONCLUSIONS: We aimed to build a visual analytics-oriented web server to detect and visualize common motifs at the protein-ligand interface. visGReMLIN motifs can support users in gaining insights on the key atoms/residues responsible for protein-ligand interactions in a dataset of complexes.


Assuntos
Ligantes , Proteínas/metabolismo , Interface Usuário-Computador , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligação Proteica , Proteínas/química
19.
PLoS One ; 15(3): e0229730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119710

RESUMO

The tryptophan hydroxylase 2 (TPH2) enzyme catalyzes the first step of serotonin biosynthesis. Serotonin is known for its role in several homeostatic systems related to sleep, mood, and food intake. As the reaction catalyzed by TPH2 is the rate-limiting step of serotonin biosynthesis, mutations in TPH2 have been associated with several psychiatric disorders (PD). This work undertakes an in silico analysis of the effects of genetic mutations in the human TPH2 protein. Ten algorithms were used to predict the functional and stability effects of the TPH2 mutations. ConSurf was used to estimate the evolutionary conservation of TPH2 amino acids. GROMACS was used to perform molecular dynamics (MD) simulations of TPH2 WT and P260S, R303W, and R441H, which had already been associated with the development of PD. Forty-six TPH2 variants were compiled from the literature. Among the analyzed variants, those occurring at the catalytic domain were shown to be more damaging to protein structure and function. The ConSurf analysis indicated that the mutations affecting the catalytic domain were also more conserved throughout evolution. The variants S364K and S383F were predicted to be deleterious by all the functional algorithms used and occurred at conserved positions, suggesting that they might be deleterious. The MD analyses indicate that the mutations P206S, R303W, and R441H affect TPH2 flexibility and essential mobility at the catalytic and oligomerization domains. The variants P206S, R303W, and R441H also exhibited alterations in dimer binding affinity and stability throughout the simulations. Thus, these mutations may impair TPH2 functional interactions and, consequently, its function, leading to the development of PD. Furthermore, we developed a database, SNPMOL (http://www.snpmol.org/), containing the results presented in this paper. Understanding the effects of TPH2 mutations on protein structure and function may lead to improvements in existing treatments for PD and facilitate the design of further experiments.


Assuntos
Simulação por Computador , Transtornos Mentais/enzimologia , Transtornos Mentais/genética , Mutação/genética , Triptofano Hidroxilase/química , Triptofano Hidroxilase/genética , Sequência Conservada , Cristalografia por Raios X , Estabilidade Enzimática , Evolução Molecular , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Análise de Componente Principal , Estrutura Secundária de Proteína
20.
Food Chem ; 318: 126404, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32135426

RESUMO

The physicochemical properties of collagen casings were successfully improved by glutaraldehyde (GA) cross-linking, where the properties could be further regulated by drying temperature. Transverse direction (TD) showed a lower heat shrinkage rate than that in machine direction (MD). GA cross-linking significantly improved the mechanical properties of films under wet and boiled state. The mechanical properties of films in MD were more susceptible to wet and boiling water. The chemical composition was unchanged after GA cross-linking, but higher drying temperatures led to higher triple helix contents. The GA cross-linking mainly promoted the low temperature thermostability of collagen casings. All film samples had a rough fibrous morphology and a majority of collagen fibers was oriented under the lower drying temperature (55 â„ƒ). These results reported in this study can be used to better guide the preparation of collagen casings.


Assuntos
Colágeno/química , Reagentes para Ligações Cruzadas/química , Glutaral/química , Animais , Dessecação , Módulo de Elasticidade , Ligação de Hidrogênio , Conformação Proteica em alfa-Hélice , Estabilidade Proteica , Temperatura
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