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1.
J Chem Phys ; 151(12): 124706, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31575160

RESUMO

Most theories of the binding of molecules to surfaces or for the association between molecules treat the binding species as structureless entities and neglect their rigidity and the changes in their stiffness induced by the binding process. The binding species are also taken to be "ideal," meaning that the existence of van der Waals interactions and changes in these interactions upon molecular binding are also neglected. An understanding of the thermodynamics of these multifunctional molecular binding processes has recently come into focus in the context of the molecular binding of complex molecules, such as dendrimers and DNA grafted nanoparticles, to surfaces where the degree of binding cooperativity and selectivity, as well as the location of the binding transition, are found to be sensitive to the number of binding units constrained to a larger scale polymeric scaffold. We address the fundamental problem of molecular binding by extending classical Langmuir theory to describe the particular example of the reversible binding of semiflexible polymer chains to a solid substrate under melt conditions. The polymer chains are assumed to have a variable number N of binding units (segments) and to exhibit variable bending energies and van der Waals interactions in the bulk and on the surface, in addition to strong directional interactions with the surface. The resulting generalized Langmuir theory is applied to the examination of the influence of the chain connectivity of ideal polymers on the surface coverage Θ, transition binding temperature T1/2 at which Θ = 1/2, and on the derivative |dΘ/dT|T=T1/2 and the constant volume specific heat of binding, Cv bind, measures of the cooperativity and "sharpness" of the binding transition, respectively. Paper II is devoted to the impact of the van der Waals attractive interactions and chain stiffness on the reversible binding of nonideal polymer chains to a solid surface, including the enthalpy-entropy compensation phenomenon observed experimentally in many molecular and particle binding processes.


Assuntos
Modelos Químicos , Polímeros/química , Adsorção , Congelamento , Termodinâmica
2.
Water Sci Technol ; 80(2): 339-346, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31537770

RESUMO

In this work, the integration of dynamic bioenergetic calculations in the IWA Anaerobic Digestion Model No. 1 (ADM1) is presented. The impact of bioenergetics on kinetics was addressed via two different approaches: a thermodynamic-based inhibition function and variable microbial growth yields based on dynamic Gibbs free energy calculations. The dynamic bioenergetic calculations indicate that the standard ADM1 predicts positive reaction rates under thermodynamically unfeasible conditions. The dissolved hydrogen inhibition approach used in ADM1 is, however, deemed as adequate, offering the trade-off of not requiring dynamic bioenergetics computation despite the need of hydrogen inhibition parameters. Simulations of the model with bioenergetics showed the low amount of energy available in butyrate and propionate oxidation, suggesting that microbial growth on these substrates must be very limited or occur via alternative mechanisms rather than dissolved hydrogen.


Assuntos
Anaerobiose , Modelos Teóricos , Reatores Biológicos , Hidrogênio , Cinética , Termodinâmica
3.
Bioresour Technol ; 293: 122056, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31514117

RESUMO

Aiming at optimizing the adsorption process of Chlorella vulgaris and cationic starch, the adsorption thermodynamic characteristics were evaluated. Different from inorganic calcium salt adsorbent, the adsorption nature of organic polymer cationic starch is exothermic (ΔH°â€¯< 0) and spontaneous (ΔG°â€¯< 0). Besides, the adsorption capacity and rate can be well described by Langmiur isotherm and pseudo second kinetic models. As results of exothermic nature and great driving force of lower temperature, the adsorption capacity and rate declined with the rising temperature. The maximal values of them were obtained at 278.15 K, which were 9148.14 mg microalgae (g cationic starch)-1 and 8.74 × 10-6 mg g-1 min-1. Additionally, with insufficient adsorbent, the highest adsorption efficiency (96.37%) was achieved at 278.15 K for stirring 150 min. For 288.15, 298.15, 308.15 and 318.15 K, the adsorption efficiency decreased to 93.77%, 86.75%, 83.32% and 81.57% and the time consumed were at least 40 min longer.


Assuntos
Chlorella vulgaris , Adsorção , Concentração de Íons de Hidrogênio , Cinética , Polímeros , Amido , Temperatura Ambiente , Termodinâmica
4.
Phys Chem Chem Phys ; 21(37): 20840-20848, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31517382

RESUMO

The room temperature pump-probe X-ray free electron laser (XFEL) measurements used for serial femtosecond crystallography provide remarkable information about the structures of the catalytic (S-state) intermediates of the oxygen-evolution reaction of photosystem II. However, mixed populations of these intermediates and moderate resolution limit the interpretation of the data from current experiments. The S3 XFEL structures show extra density near the OEC that may correspond to a water/hydroxide molecule. However, in the latest structure, this additional oxygen is 2.08 Šfrom the Oε2 of D1-E189, which is closer than the sum of the van der Waals radii of the two oxygens. Here, we use Boltzmann statistics and Monte Carlo sampling to provide a model for the S2-to-S3 state transition, allowing structural changes and the insertion of an additional water/hydroxide. Based on our model, water/hydroxide addition to the oxygen-evolving complex (OEC) is not thermodynamically favorable in the S2g = 2 state, but it is in the S2g = 4.1 redox isomer. Thus, formation of the S3 state starts by a transition from the S2g = 2 to the S2g = 4.1 structure. Then, electrostatic interactions support protonation of D1-H190 and deprotonation of the Ca2+-ligated water (W3) with proton loss to the lumen. The W3 hydroxide moves toward Mn4, completing the coordination shell of Mn4 and favoring its oxidation to Mn(iv) in the S3 state. In addition, binding an additional hydroxide to Mn1 leads to a conformational change of D1-E189 in the S2g = 4.1 and S3 structures. In the S3 state a fraction of D1-E189 release from Mn1 and bind a proton.


Assuntos
Modelos Químicos , Oxigênio/química , Complexo de Proteína do Fotossistema II/química , Termodinâmica
5.
J Chem Phys ; 151(7): 074903, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438701

RESUMO

Ionic microgels are soft colloidal particles, composed of crosslinked polymer networks, which ionize and swell when dispersed in a good solvent. Swelling of these permeable, compressible particles involves a balance of electrostatic, elastic, and mixing contributions to the single-particle osmotic pressure. The electrostatic contribution depends on the distributions of mobile counterions and coions and of fixed charge on the polymers. Within the cell model, we employ two complementary methods to derive the electrostatic osmotic pressure of ionic microgels. In Poisson-Boltzmann (PB) theory, we minimize a free energy functional with respect to the electrostatic potential to obtain the bulk pressure. From the pressure tensor, we extract the electrostatic and gel contributions to the total pressure. In a statistical mechanical approach, we vary the free energy with respect to microgel size to obtain exact relations for the microgel electrostatic osmotic pressure. We present results for planar, cylindrical, and spherical geometries. For models of membranes and microgels with fixed charge uniformly distributed over their surface or volume, we derive analogs of the contact value theorem for charged colloids. We validate these relations by solving the PB equation and computing ion densities and osmotic pressures. When implemented within PB theory, the two methods yield identical electrostatic osmotic pressures for surface-charged microgels. For volume-charged microgels, the exact electrostatic osmotic pressure equals the average of the corresponding PB profile over the gel volume. We demonstrate that swelling of ionic microgels depends on the variation of the electrostatic pressure inside the particle and discuss implications for interpreting experiments.


Assuntos
Modelos Teóricos , Pressão Osmótica , Géis , Permeabilidade , Eletricidade Estática , Termodinâmica
6.
Phys Chem Chem Phys ; 21(32): 17821-17835, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31373340

RESUMO

The rise of New Delhi metallo-beta-lactamase-1 (NDM-1) producers is a major public health concern due to carbapenem resistance. Infections caused by carbapenem-resistant enterobacteria (CRE) are classified as a serious problem. To understand the structure and function of NDM-1, an amino acid replacement approach is considered as one of the methods to get structural insight. Therefore, we have generated novel mutations (N193A, S217A, G219A and T262A) near active sites and an omega-like loop to study the role of conserved residues of NDM-1. The minimum inhibitory concentrations (MICs) of ampicillin, imipenem, meropenem, cefotaxime, cefoxitin and ceftazidime for all mutants were found to be reduced 2 to 6 fold, compared to a wild type NDM-1 producing strain. The Km values increased while Kcat and Kcat/Km values were decreased compared to wild type. The affinity as well as the catalysis properties of these mutants were reduced considerably for imipenem, meropenem, cefotaxime, cefoxitin, and ceftazidimem compared to wild type, hence the catalytic efficiencies (Kcat/Km) of all mutant enzymes were reduced owing to the poor affinity of the enzyme. The IC50 values of these mutants with respect to each drug were reduced compared to wild type NDM-1. MD simulations and docking results from the mutant protein models, along with the wild type example, showed stable and consistent RMSD, RMSF and Rg behavior. The α-helix content values of all mutant proteins were reduced by 13%, 6%, 14% and 9% compared to NDM-1. Hence, this study revealed the impact role of active sites near residues on the enzyme catalytic activity of NDM-1.


Assuntos
Antibacterianos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , beta-Lactamases/química , Antibacterianos/farmacologia , Biocatálise , Domínio Catalítico , Farmacorresistência Bacteriana , Cinética , Testes de Sensibilidade Microbiana , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Estrutura Secundária de Proteína , Termodinâmica , beta-Lactamases/genética , beta-Lactamases/metabolismo
7.
Phys Chem Chem Phys ; 21(32): 17893-17900, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31380529

RESUMO

The dispersion interaction was reported to play a critical role in the stabilization of model dipeptide Z-Arg-OH, even greater than the conventional hydrogen bond (HB), which is opposite to the traditional opinion. Here the conformation of Z-Arg-OH has been systematically searched by the effective fragment based step-by-step strategy. All the newly-found low-energy conformers determined at the advanced DSD-PBEP86-D3(BJ)/aug-cc-pVTZ level are clearly in the stretched form with strong conventional HBs, rather than the reported folded structures with emphasis on the dispersion interactions. The simulated IR spectra of the stretched conformers fit better than those of the folded ones compared with the previous experimental observations. Near-edge X-ray absorption fine-structure (NEXAFS) spectra and X-ray photoelectron spectra (XPS) at C, N and O K-edges have also been simulated to unambiguously identify different isomers. This work thus provides valuable insight into the competitions between the conventional HB and the dispersion interactions and demonstrates that the conventional hydrogen bonding is still more important for such small peptides.


Assuntos
Arginina/análogos & derivados , Arginina/química , Dipeptídeos/química , Modelos Moleculares , Ligações de Hidrogênio , Isomerismo , Fenômenos Físicos , Conformação Proteica , Estabilidade Proteica , Solventes/química , Termodinâmica
8.
Phys Chem Chem Phys ; 21(32): 17971-17977, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31384846

RESUMO

The electron-hole injection from a family of spiropyran photoswitches into A/T-duplex DNA has been investigated at the molecular level for the first time. Multiscale computations coupled with automatized quantitative wavefunction analysis reveal a pronounced directionality and regioselectivity towards the template strand of the duplex DNA. Our findings suggest that this directional and regioselective photoinduced electron-hole transfer could thus be exploited to tailor the charge transport processes in DNA in specific applications.


Assuntos
Benzopiranos/química , DNA/química , Indóis/química , Substâncias Intercalantes/química , Nitrocompostos/química , Transporte de Elétrons , Luz , Modelos Moleculares , Conformação de Ácido Nucleico , Oxirredução , Processos Fotoquímicos , Prótons , Termodinâmica
9.
Phys Chem Chem Phys ; 21(32): 17950-17958, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31384849

RESUMO

The A. aeolicus intrinsically disordered protein FlgM has four well-defined α-helices when bound to σ28, but in water FlgM undergoes a change in tertiary structure. In this work, we investigate the structure of FlgM in aqueous solutions of the ionic liquid [C4mpy][Tf2N]. We find that FlgM is induced to fold by the addition of the ionic liquid, achieving average α-helicity values similar to the bound state. Analysis of secondary structure reveals significant similarity with the bound state, but the tertiary structure is found to be more compact. Interestingly, the ionic liquid is not homogeneously dispersed in the water, but instead aggregates near the protein. Separate simulations of aqueous ionic liquid do not show ion clustering, which suggests that FlgM stabilizes ionic liquid aggregation.


Assuntos
Proteínas de Bactérias/química , Imidas/química , Proteínas Intrinsicamente Desordenadas/química , Líquidos Iônicos/química , Modelos Moleculares , Pirrolidinas/química , Bases de Dados de Proteínas , Conformação Proteica em alfa-Hélice , Dobramento de Proteína , Termodinâmica , Água
10.
Bioresour Technol ; 291: 121892, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31376670

RESUMO

The aim of this study was to investigate the bioenergy potential of red macroalgae GF by evaluating its biofuel physicochemical characteristics, and conducting a kinetic study and thermodynamic analysis of pyrolysis for the first time. The thermal decomposition study was performed at low heating rates (5, 10, 20 and 30 °C min-1) under N2 atmosphere. The thermal behavior of GF pyrolysis indicated the presence of three different decomposition stages, which are associated with different components in its structure and consequently influence the kinetic and thermodynamic parameters. The kinetic triplet obtained for GF provided a suitable description of experimental thermal behavior. The thermodynamic parameters demonstrated that GF is as a new promising feedstock for bioenergy and presented a similar potential to well-known bioenergy feedstock.


Assuntos
Rodófitas/metabolismo , Alga Marinha/metabolismo , Termodinâmica , Biocombustíveis , Cinética , Pirólise
11.
Pharm Res ; 36(10): 150, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31428879

RESUMO

PURPOSE: The unconventional tabletability of the indomethacin polymorphs - α and γ - are investigated from a topological and mechanical perspective using powder Brillouin light scattering (p-BLS) to identify the specific structure-performance relationship in these materials. METHOD: Indomethacin (γ-form) was purchased and used to prepare the α polymorph. Powder X-ray diffraction was used to confirm phase identity, while p-BLS was used to obtain the mechanical properties. Energy frameworks were determined with Crystal Explorer to visualize the interaction topologies. Using a Carver press and a stress-strain analyzer, the tableting performance of each polymorph was determined. RESULTS: Polymorph-specific acoustic frequency distributions were observed with distinct, zero-porosity, aggregate elastic moduli determined. The p-BLS spectra for α-indomethacin display a population of low-velocity shear modes, indicating a direction of facilitated shear. This improves slip-mediated plasticity and tabletability. Our p-BLS spectra experimentally indicates that a low-energy slip system is available to α-indomethacin which supports ours and previous energy framework calculations. Despite a 2d-layered crystal motif favorable for shear deformation, the γ-form displays a higher shear modulus that is supported by our hydrogen-bonding analysis of γ-indomethacin. CONCLUSION: Our experimental, mechanical data is consistent with the predicted interaction topologies and these two inputs combined permit a comprehensive, molecular understanding of polymorph-specific tabletability.


Assuntos
Indometacina/química , Cristalização , Dimerização , Composição de Medicamentos , Ligações de Hidrogênio , Luz , Fenômenos Mecânicos , Porosidade , Pós , Espalhamento de Radiação , Comprimidos , Termodinâmica
12.
J Chem Theory Comput ; 15(9): 5135-5143, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31390206

RESUMO

Predicting the assembly of multiple proteins into specific complexes is critical to understanding their biological function in an organism and thus the design of drugs to address their malfunction. Proteins are flexible molecules, which inherently pose a problem to any protein docking computational method, where even a simple rearrangement of the side chain and backbone atoms at the interface of binding partners complicates the successful determination of the correct docked pose. Herein, we present a means of representing protein surface, electrostatics, and local dynamics within a single volumetric descriptor. We show that our representations can be physically related to the surface-accessible solvent area and mass of the protein. We then demonstrate that the application of this representation into a protein-protein docking scenario bypasses the need to compensate for, and predict, specific side chain packing at the interface of binding partners. This representation is leveraged in our de novo protein docking software, JabberDock, which can accurately and robustly predict difficult target complexes with an average success rate of >54%, which is comparable to or greater than the currently available methods.


Assuntos
Simulação de Acoplamento Molecular , Proteínas/química , Eletricidade Estática , Termodinâmica , Ligação Proteica , Propriedades de Superfície
13.
J Enzyme Inhib Med Chem ; 34(1): 1451-1456, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31409143

RESUMO

Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, p = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC50, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.


Assuntos
Inibidores da Protease de HIV/farmacologia , Protease de HIV/efeitos dos fármacos , HIV-1/enzimologia , Termodinâmica , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Mutação
14.
Water Sci Technol ; 79(12): 2337-2344, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31411588

RESUMO

Acidic content in wastewaters poses greater difficulty in lead removal from most adsorbents as their removal efficiency significantly decreases in acidic media. Nano-nickel coated carbon (Ni/C), compared with uncoated carbon (C), has shown a much enhanced (almost 80% higher) tendency of Pb(II) removal from solutions having different acid concentrations. All of the characterization results show the creation of more active sites and functional groups on Ni/C. The pertinent kinetic models and thermodynamics of Pb(II) adsorption have demonstrated much improved efficiency by Ni/C. Various isotherms subjected to the sorption data revealed significant increase in the sorption capacities for Ni/C. The adsorption (evidently chemisorption) kinetics are best represented by a pseudo-second-order equation. The adsorption rates in acidic solutions were much higher for Ni/C. The temperature-dependent study enabled thermodynamic parameters to be worked out for C and Ni/C; for C the values are ΔH: 19.4 ± 0.5 kJ·mol-1, ΔS: 76.1 ± 2.1 J·mol-1·K-1, ΔG298: -0.37 ± 0.01 kJ·mol-1 while for Ni/C the values are ΔH: 30 ± 1 kJ·mol-1, ΔS: 114 ± 4 J·mol-1·K-1, ΔG298: -4.56 ± 0.02 kJ·mol-1. Both cases indicate endothermic, spontaneous and entropy-driven processes.


Assuntos
Chumbo , Níquel , Adsorção , Carbono , Concentração de Íons de Hidrogênio , Cinética , Modelos Químicos , Termodinâmica
15.
Soft Matter ; 15(33): 6630-6641, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31403143

RESUMO

The mechanics of blister delamination and growth plays a major role in a diversity of areas including medicine (skin pathology and mechanics of cell membranes), materials (adhesive and fracture) or soft robotics (actuation and morphing). The behavior of a blister in this context is typically difficult to grasp as it arises from the interplay of two highly nonlinear and time-dependent processes: membrane attachment and decohesion from a substrate. In the present work, we device a simplified approach, based on experimental systems, to predict the deformation path of a blister under various conditions. For this, we consider the problem of a growing blister made of a rubber-like membrane adhered on a rigid substrate, and develop a theoretical and experimental framework to study its stability and growth. We start by constructing a theoretical model of viscoelastic blister growth which we later validate with an experimental setup. We show that blister growth is controlled by the competition between two instabilities: one inherent to the rubber, and a second one pertaining to the adhesion with the substrate. Using these concepts, we show that a "targeted" stable blister shape can be achieved by controlling two parameters: the thickness of the film and the inflation rate.


Assuntos
Simulação por Computador , Membranas Artificiais , Modelos Teóricos , Adsorção , Elasticidade , Cinética , Propriedades de Superfície , Termodinâmica , Viscosidade
16.
Inorg Chem ; 58(17): 11782-11792, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31433630

RESUMO

Reproduction of the dominant vector of Zika and dengue diseases, Aedes aegypti mosquito, is controlled by an active heterodimer complex composed of the 20-hydroxyecdysone receptor (EcR) and ultraspiracle protein. Although A. aegypti EcR shares the structural and functional organization with other nuclear receptors, its C-terminus has an additional long F domain (AaFEcR). Recently, we showed that the full length AaFEcR is intrinsically disordered with the ability to specifically bind divalent metal ions. Here, we describe the details of the exhaustive structural and thermodynamic properties of Zn2+- and Cu2+-complexes with the AaFEcR domain, based on peptide models of its two putative metal binding sites (Ac-HGPHPHPHG-NH2 and Ac-QQLTPNQQQHQQQHSQLQQVHANGS-NH2). Unexpectedly, only in the presence of increasing concentrations of Cu2+ ions, the Ac-HGPHPHPHG-NH2 peptide gained a metal ion-induced poly-l-proline type II helical structure, which is unique for members of the family of nuclear receptors.


Assuntos
Aedes/efeitos dos fármacos , Antivirais/farmacologia , Cobre/farmacologia , Compostos Organometálicos/farmacologia , Peptídeos/farmacologia , Receptores de Esteroides/antagonistas & inibidores , Animais , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , Cobre/química , Dengue/tratamento farmacológico , Dengue/metabolismo , Estrutura Molecular , Compostos Organometálicos/química , Peptídeos/química , Receptores de Esteroides/metabolismo , Termodinâmica , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/metabolismo
17.
Phys Chem Chem Phys ; 21(33): 18219-18226, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31389931

RESUMO

The villin headpiece subdomain (HP35) is a fast-folding protein with 35 residues and its folding pathways have been extensively studied experimentally and theoretically but remain controversial. While experiments showed that HP35 might have multiple folding pathways, most theoretical studies only found one major pathway, although a few theoretical studies revealed two. Here we report our results of molecular dynamics simulations of HP35 folding by using the newest AMBER ff14SB force field and show that HP35 has a novel folding pathway in addition to the two pathways shown previously. We also study the mechanism of determining the folding pathways and found that the dynamics of Helix2 may play a special role in the folding of HP35. Our results may be helpful to understand the folding mechanism of HP35 further.


Assuntos
Proteínas dos Microfilamentos/química , Simulação de Dinâmica Molecular , Peptídeos/química , Dobramento de Proteína , Domínios Proteicos , Termodinâmica
18.
Phys Chem Chem Phys ; 21(33): 18105-18118, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31396604

RESUMO

With the emergence of drug-resistant Plasmodium falciparum, the treatment of malaria has become a significant challenge; therefore, the development of antimalarial drugs acting on new targets is extremely urgent. In Plasmodium falciparum, type II nicotinamide adenine dinucleotide (NADH) dehydrogenase (NDH-2) is responsible for catalyzing the transfer of two electrons from NADH to flavin adenine dinucleotide (FAD), which in turn transfers the electrons to coenzyme Q (CoQ). As an entry enzyme for oxidative phosphorylation, NDH-2 has become one of the popular targets for the development of new antimalarial drugs. In this study, reliable motion trajectories of the NDH-2 complex with its co-factors (NADH and FAD) and inhibitor, RYL-552, were obtained by comparative molecular dynamics simulations. The influence of cofactor binding on the global motion of NDH-2 was explored through conformational clustering, principal component analysis and free energy landscape. The molecular interactions of NDH-2 before and after its binding with the inhibitor RYL-552 were analyzed, and the key residues and important hydrogen bonds were also determined. The results show that the association of RYL-552 results in the weakening of intramolecular hydrogen bonds and large allosterism of NDH-2. There was a significant positive correlation between the angular change of the key pocket residues in the NADH-FAD-pockets that represents the global functional motion and the change in distance between NADH-C4 and FAD-N5 that represents the electron transfer efficiency. Finally, the possible non-competitive inhibitory mechanism of RYL-552 was proposed. Specifically, the association of inhibitors with NDH-2 significantly affects the global motion mode of NDH-2, leading to widening of the distance between NADH and FAD through cooperative motion induction; this reduces the electron transfer efficiency of the mitochondrial respiratory chain. The simulation results provide useful theoretical guidance for subsequent antimalarial drug design based on the NDH-2 structure and the respiratory chain electron transfer mechanism.


Assuntos
Antimaláricos/química , Cetonas/química , NADH Desidrogenase/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Quinolinas/química , Transporte de Elétrons , Flavina-Adenina Dinucleotídeo/química , Ligações de Hidrogênio , Modelos Moleculares , Estrutura Molecular , NAD/química , NADH Desidrogenase/química , Oxirredução , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica
19.
Chem Commun (Camb) ; 55(70): 10432-10435, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31408066

RESUMO

RNA represents an extremely promising and yet challenging therapeutic target. Here, we report the design of a series of C-nucleosides as original RNA binders. Some of them bind strongly and selectively to A-site prokaryotic ribosomal RNA.


Assuntos
Nucleosídeos/metabolismo , RNA Ribossômico/metabolismo , Ribossomos/metabolismo , Dicroísmo Circular , Ressonância Magnética Nuclear Biomolecular , Conformação de Ácido Nucleico , Nucleosídeos/química , RNA Ribossômico/química , Termodinâmica
20.
Phytochemistry ; 166: 112077, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31374519

RESUMO

Radical scavenging activity and subsequent oxidation resulting in quinone products represent one of the important features of phenols occurring in plants and other biological systems. However, corresponding thermochemistry data can be still considered scarce. For phenol and 25 para-substituted phenols, we investigate the thermodynamics of the individual reaction steps, including three subsequent hydrogen atom transfers, as well as hydroxyl HO radical addition, leading to final ortho-quinone formation. The substituent and solvent effect of water on corresponding reactions enthalpies is elucidated. Solvent enhances substituent induced changes in the investigated reaction enthalpies. The reliability of employed computational methods for the thermodynamics of hydrogen atom donating ability of studied phenols and catechols is assessed, too. Obtained linear equations enable estimation of studied reaction enthalpies from Hammett constants of substituents.


Assuntos
Depuradores de Radicais Livres/química , Fenóis/química , Quinonas/química , Radical Hidroxila/química , Isomerismo , Relação Estrutura-Atividade , Termodinâmica
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