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1.
Phys Rev Lett ; 125(9): 098101, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32915604

RESUMO

Programmable valves and actuators are widely used in man-made systems to provide sophisticated control of fluid flows. In nature, however, this process is frequently achieved using passive soft materials. Here we study how elastic deformations of cylindrical pores embedded in a flexible membrane enable passive flow control. We develop biomimetic valves with variable pore radius, membrane radius, and thickness. Our experiments reveal a mechanism where small deformations bend the membrane and constrict the pore-thus reducing flow-while larger deformations stretch the membrane, expand the pore, and enhance flow. We develop a theory capturing this highly nonmonotonic behavior, and validate the scaling across a broad range of material and geometric parameters. Our results suggest that intercompartmental flow control in living systems can be encoded entirely in the physical attributes of soft materials. Moreover, this design could enable autonomous flow control in man-made systems.


Assuntos
Materiais Biomiméticos/química , Modelos Biológicos , Modelos Químicos , Animais , Membranas/química
2.
Chemosphere ; 258: 127279, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947678

RESUMO

Adsorption is widely applied separation process, especially in environmental remediation, due to its low cost and high efficiency. Adsorption isotherm models can provide mechanism information of the adsorption process, which is important for the design of adsorption system. However, the classification, physical meaning, application and solving method of the isotherms have not been systematical analyzed and summarized. In this paper, the adsorption isotherms were classified into adsorption empirical isotherms, isotherms based on Polanyi's theory, chemical adsorption isotherms, physical adsorption isotherms, and the ion exchange model. The derivation and physical meaning of the isotherm models were discussed in detail. In addition, the application of the isotherm models were analyzed and summarized based on over 200 adsorption equilibrium data in literature. The statistical parameters for evaluating the fitness of the models were also discussed. Finally, a user interface (UI) was developed based on Excel software for solving the isotherm models, which was provided in supplemental material and can be easily used to model the adsorption equilibrium data. This paper will provide theoretical basis and guiding methodology for the selection and use of the adsorption isotherms.


Assuntos
Adsorção , Modelos Químicos , Software , Termodinâmica
3.
SAR QSAR Environ Res ; 31(10): 785-801, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32878491

RESUMO

Reviewing the toxicological literature for over the past decades, the key elements of QSAR modelling have been the mechanisms of toxic action and chemical classes. As a result, it is often hard to design an acceptable single model for a particular endpoint without clustering compounds. The main aim here was to develop a Pass-Pass Quantitative Structure-Activity-Activity Relationship (PP QSAAR) model for direct prediction of the toxicity of a larger set of compounds, combing the application of an already predicted model for another species, and molecular descriptors. We investigated a large acute toxicity data set of five aquatic organisms, fish, Daphnia magna, and algae from the VEGA-Hub, as well as Tetrahymena pyriformis and Vibrio fischeri. The statistical quality of the models encouraged us to consider this alternative for the prediction of toxicity using interspecies extrapolation QSAAR models without regard to the toxicity mechanism or chemical class. In the case of algae, the use of activity values from a second species did not improve the models. This can be attributed to the weak interspecies relationships, due to different aquatic toxicity mechanisms in species.


Assuntos
Organismos Aquáticos/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Testes de Toxicidade Aguda , Poluentes Químicos da Água/toxicidade , Aliivibrio fischeri/efeitos dos fármacos , Animais , Daphnia/efeitos dos fármacos , Peixes , Regulamentação Governamental , Microalgas/efeitos dos fármacos , Modelos Químicos , Medição de Risco , Tetrahymena pyriformis/efeitos dos fármacos
4.
SAR QSAR Environ Res ; 31(10): 741-759, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32892643

RESUMO

The human immunodeficiency virus is a lethal pathology considered as a worldwide problem. The search for new strategies for the treatment of this disease continues to be a great challenge in the scientific community. In this study, a series of 107 derivatives of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine, previously evaluated experimentally against HIV-I reverse transcriptase, was used to model antiretroviral activity. A model of linear regression, implemented in the QSARINS software, was developed with a genetic algorithm for variable selection. The fit of its parameters was good and exhaustive validation, according to the OECD regulatory principles, was performed. Also, the applicability domain was established. In addition, its robustness (r 2 = 0.84), stability (Q 2 LOO = 0.81; Q 2 LMO = 0.80) and good predictive power (r 2 EXT = 0.85) is proved. So, it was used to predict the antiretroviral activity of eight compounds obtained by rational drug design. Finally, it can be affirmed that the proposed tools allow the rapid and economic identification of potential antiretroviral drugs.


Assuntos
Antirretrovirais/química , Relação Quantitativa Estrutura-Atividade , Timina/análogos & derivados , Modelos Químicos , Organização para a Cooperação e Desenvolvimento Econômico/normas , Timina/química
5.
Chemosphere ; 254: 126869, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957283

RESUMO

This paper presents the results of Co(II) and Ni(II) extraction from model and real solutions using bis(2,4,4-trimethylpentyl)phosphinic acid (i.e. Cyanex 272) that are in agreement with waste-to-resources approach, i.e. the recovery of valuable components from wastes. The results from this study shows that, extraction using Cyanex 272 is an efficient method to recover Co(II) selectively from sulfate electrolytes obtained from the leaching of steel scraps of aircraft engines. The highest selectivity value (∼160) of Co(II) extraction over Ni(II) was obtained at a pH of 4.8, the lowest selectivity value (∼30) was observed at a pH of 5.5, while above this value the selectivity only increased slightly with increasing pH. A pH of 5.2 was selected as a compromise between Co(II) selectivity and Ni(II) amount in the organic phase. The essence of the investigation is to propose important parameters to extract Co(II) from real leach solutions, and to further recover valuable Co(II) from the loaded organic phase by stripping with 1 M H2SO4, thus producing an electrolyte of Co(II) for electrowinning - a possible alternative route for resource recovery. Small volume of the stripping phase (w/o = 1:5) used in this study, lead to an enrichment of sulfate electrolyte in Co(II), resulting in ∼50 g/dm3 of Co(II) in the solution, which is a great advantage of the approach proposed. Such a solution is a valuable source for the electrowinning of metallic cobalt, which can be used for the production of steel alloys, Li-ion batteries or catalysts.


Assuntos
Cobalto/química , Modelos Químicos , Níquel/química , Ácidos Fosfínicos/química , Fontes de Energia Elétrica , Lítio , Sulfatos
6.
Phys Rev Lett ; 125(5): 058001, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32794838

RESUMO

Glassy, nonexponential relaxations in globular proteins are typically attributed to conformational behaviors that are missing from intrinsically disordered proteins. Yet, we show that single molecules of a disordered-protein construct display two signatures of glassy dynamics, logarithmic relaxations and a Kovacs memory effect, in response to changes in applied tension. We attribute this to the presence of multiple independent local structures in the chain, which we corroborate with a model that correctly predicts the force dependence of the relaxation. The mechanism established here likely applies to other disordered proteins.


Assuntos
Modelos Químicos , Proteínas de Neurofilamentos/química , Cisteína/química , Cinética , Dobramento de Proteína , Termodinâmica
7.
Phys Rev Lett ; 125(5): 058103, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32794851

RESUMO

Many complex systems, ranging from migrating cells to animal groups, exhibit stochastic dynamics described by the underdamped Langevin equation. Inferring such an equation of motion from experimental data can provide profound insight into the physical laws governing the system. Here, we derive a principled framework to infer the dynamics of underdamped stochastic systems from realistic experimental trajectories, sampled at discrete times and subject to measurement errors. This framework yields an operational method, Underdamped Langevin Inference, which performs well on experimental trajectories of single migrating cells and in complex high-dimensional systems, including flocks with Viscek-like alignment interactions. Our method is robust to experimental measurement errors, and includes a self-consistent estimate of the inference error.


Assuntos
Modelos Teóricos , Movimento , Animais , Comportamento Animal/fisiologia , Movimento Celular/fisiologia , Poeira , Modelos Biológicos , Modelos Químicos , Movimento/fisiologia , Dinâmica não Linear , Densidade Demográfica
8.
Phys Rev Lett ; 125(6): 068102, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32845671

RESUMO

We quantified the equilibrium (un)folding free energy ΔG_{0} of an eight-amino-acid region starting from the fully folded state of the model membrane-protein bacteriorhodopsin using single-molecule force spectroscopy. Analysis of equilibrium and nonequilibrium data yielded consistent, high-precision determinations of ΔG_{0} via multiple techniques (force-dependent kinetics, Crooks fluctuation theorem, and inverse Boltzmann analysis). We also deduced the full 1D projection of the free-energy landscape in this region. Importantly, ΔG_{0} was determined in bacteriorhodopsin's native bilayer, an advance over traditional results obtained by chemical denaturation in nonphysiological detergent micelles.


Assuntos
Bacteriorodopsinas/química , Modelos Químicos , Microscopia de Força Atômica , Dobramento de Proteína , Termodinâmica
9.
Phys Rev Lett ; 125(7): 078102, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32857533

RESUMO

Diffusion-mediated surface phenomena are crucial for human life and industry, with examples ranging from oxygen capture by lung alveolar surface to heterogeneous catalysis, gene regulation, membrane permeation, and filtration processes. Their current description via diffusion equations with mixed boundary conditions is limited to simple surface reactions with infinite or constant reactivity. In this Letter, we propose a probabilistic approach based on the concept of boundary local time to investigate the intricate dynamics of diffusing particles near a reactive surface. Reformulating surface-particle interactions in terms of stopping conditions, we obtain in a unified way major diffusion-reaction characteristics such as the propagator, the survival probability, the first-passage time distribution, and the reaction rate. This general formalism allows us to describe new surface reaction mechanisms such as for instance surface reactivity depending on the number of encounters with the diffusing particle that can model the effects of catalyst fooling or membrane degradation. The disentanglement of the geometric structure of the medium from surface reactivity opens far-reaching perspectives for modeling, optimization, and control of diffusion-mediated surface phenomena.


Assuntos
Modelos Biológicos , Modelos Químicos , Membrana Celular/química , DNA/química , Difusão , Proteínas/química , Propriedades de Superfície , Termodinâmica
10.
Phys Rev Lett ; 125(7): 078101, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32857554

RESUMO

The friction between cytoskeletal filaments is of central importance for the formation of cellular structures such as the mitotic spindle and the cytokinetic ring. This friction is caused by passive cross-linkers, yet the underlying mechanism and the dependence on cross-linker density are poorly understood. Here, we use theory and computer simulations to study the friction between two filaments that are cross-linked by passive proteins, which can hop between discrete binding sites while physically excluding each other. The simulations reveal that filaments move via rare discrete jumps, which are associated with free-energy barrier crossings. We identify the reaction coordinate that governs the relative microtubule movement and derive an exact analytical expression for the free-energy barrier and the friction coefficient. Our analysis not only elucidates the molecular mechanism underlying cross-linker-induced filament friction, but also predicts that the friction coefficient scales superexponentially with the density of cross-linkers.


Assuntos
Citoesqueleto/química , Citoesqueleto/fisiologia , Modelos Biológicos , Modelos Químicos , Proteínas Motores Moleculares/química , Proteínas Motores Moleculares/fisiologia , Sítios de Ligação , Citoesqueleto/metabolismo , Fricção , Microtúbulos/química , Microtúbulos/metabolismo , Proteínas Motores Moleculares/metabolismo , Termodinâmica
11.
J Comput Chem ; 41(24): 2158-2161, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32779780

RESUMO

D614G spike glycoprotein (sgp) mutation in rapidly spreading severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) is associated with enhanced fitness and higher transmissibility in new cases of COVID-19 but the underlying mechanism is unknown. Here, using atomistic simulation, a plausible mechanism has been delineated. In G614 sgp but not wild type, increased D(G)614-T859 Cα-distance within 65 ns is interpreted as S1/S2 protomer dissociation. Overall, ACE2-binding, post-fusion core, open-state and sub-optimal antibody-binding conformations were preferentially sampled by the G614 mutant, but not wild type. Furthermore, in the wild type, only one of the three sgp chains has optimal communication route between residue 614 and the receptor-binding domain (RBD); whereas, two of the three chains communicated directly in G614 mutant. These data provide evidence that D614G sgp mutant is more available for receptor binding, cellular invasion and reduced antibody interaction; thus, providing framework for enhanced fitness and higher transmissibility in D614G SARS-COV-2 mutant.


Assuntos
Betacoronavirus/metabolismo , Simulação por Computador , Infecções por Coronavirus/virologia , Modelos Químicos , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Modelos Moleculares , Mutação , Pandemias , Ligação Proteica , Conformação Proteica , Domínios Proteicos
12.
Phys Chem Chem Phys ; 22(33): 18272-18283, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32756685

RESUMO

The COVID-19 pandemic poses a severe threat to human health with unprecedented social and economic disruption. Spike (S) glycoprotein in the SARS-CoV-2 virus is pivotal in understanding the virus anatomy, since it initiates the early contact with the ACE2 receptor in the human cell. The subunit S1 in chain A of S-protein has four structural domains: the receptor binding domain (RBD), the n-terminal domain (NTD) and two subdomains (SD1, SD2). We report details of the intra- and inter-molecular binding mechanism of RBD using density functional theory, including electronic structure, interatomic bonding and partial charge distribution. We identify five strong hydrogen bonds and analyze their roles in binding. This provides a pathway to a quantum-chemical understanding of the interaction between the S-protein and the ACE2 receptor with insights into the function of conserved features in the ACE2 receptor binding domain that could inform vaccine and drug development.


Assuntos
Betacoronavirus/química , Peptidil Dipeptidase A/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Teoria da Densidade Funcional , Humanos , Ligação de Hidrogênio , Modelos Químicos , Peptidil Dipeptidase A/química , Ligação Proteica , Domínios Proteicos , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química
13.
J Chem Phys ; 153(7): 075101, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32828084

RESUMO

In 2020, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide and caused the coronavirus disease 2019 (COVID-19). Spike (S) glycoproteins on the viral membrane bind to ACE2 receptors on the host cell membrane and initiate fusion, and S protein is currently among the primary drug target to inhibit viral entry. The S protein can be in a receptor inaccessible (closed) or accessible (open) state based on down and up positions of its receptor-binding domain (RBD), respectively. However, conformational dynamics and the transition pathway between closed to open states remain unexplored. Here, we performed all-atom molecular dynamics (MD) simulations starting from closed and open states of the S protein trimer in the presence of explicit water and ions. MD simulations showed that RBD forms a higher number of interdomain interactions and exhibits lower mobility in its down position than its up position. MD simulations starting from intermediate conformations between the open and closed states indicated that RBD switches to the up position through a semi-open intermediate that potentially reduces the free energy barrier between the closed and open states. Free energy landscapes were constructed, and a minimum energy pathway connecting the closed and open states was proposed. Because RBD-ACE2 binding is compatible with the semi-open state, but not with the closed state of the S protein, we propose that the formation of the intermediate state is a prerequisite for the host cell recognition.


Assuntos
Betacoronavirus/química , Glicoproteína da Espícula de Coronavírus/química , Sítios de Ligação , Ligação de Hidrogênio , Modelos Químicos , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Análise de Componente Principal , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Receptores Virais/química , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica
14.
Front Immunol ; 11: 1663, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754160

RESUMO

A recent pandemic caused by a single-stranded RNA virus, COVID-19, initially discovered in China, is now spreading globally. This poses a serious threat that needs to be addressed immediately. Genome analysis of SARS-CoV-2 has revealed its close relation to SARS-coronavirus along with few changes in its spike protein. The spike protein aids in receptor binding and viral entry within the host and therefore represents a potential target for vaccine and therapeutic development. In the current study, the spike protein of SARS-CoV-2 was explored for potential immunogenic epitopes to design multi-epitope vaccine constructs. The S1 and S2 domains of spike proteins were analyzed, and two vaccine constructs were prioritized with T-cell and B-cell epitopes. We adapted a comprehensive predictive framework to provide novel insights into immunogenic epitopes of spike proteins, which can further be evaluated as potential vaccine candidates against COVID-19. Prioritized epitopes were then modeled using linkers and adjuvants, and respective 3D models were constructed to evaluate their physiochemical properties and their possible interactions with ACE2, HLA Superfamily alleles, TLR2, and TLR4.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Sequência de Aminoácidos , Infecções por Coronavirus/virologia , Epitopos de Linfócito B/química , Epitopos de Linfócito T/química , Antígenos HLA/química , Antígenos HLA/imunologia , Humanos , Modelos Químicos , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/virologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Glicoproteína da Espícula de Coronavírus/imunologia , Receptor 2 Toll-Like/química , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/química , Receptor 4 Toll-Like/imunologia , Vacinas Virais/química
15.
Nat Commun ; 11(1): 4170, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820174

RESUMO

Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. However, it is a great challenge to install desired functional groups on both sides of sulfur-sulfur bonds at liberty. Herein, we designed a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of polysulfides. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol-1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Life-related molecules, natural products and pharmaceuticals can be successively cross-linked with sulfur-sulfur bond. Remarkably, the cyclization of tri- and tetra-peptides affords 15- and 18-membered cyclic disulfide peptides with this reagent, respectively.


Assuntos
Dissulfetos/química , Indicadores e Reagentes/química , Peptídeos/química , Sulfetos/química , Enxofre/química , Produtos Biológicos/química , Técnicas de Química Sintética/métodos , Ciclização , Indicadores e Reagentes/síntese química , Modelos Químicos , Estrutura Molecular , Oxirredução , Preparações Farmacêuticas/química
16.
PLoS One ; 15(8): e0237789, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810188

RESUMO

Aquaporins are water-permeable membrane-channel proteins found in biological cell membranes that selectively exclude ions and large molecules and have high water permeability, which makes them promising candidates for water desalination systems. To effectively apply the properties of aquaporins in the desalination process, many studies have been conducted on aquaporin-lipid membrane systems using phospholipids, which are the main component of cell membranes. Many parametric studies have evaluated the permeability of such systems with various aquaporin types and lipid compositions. In this study, we performed molecular dynamics simulations for four cases with different protein-lipid molar ratios (1:50, 1:75, 1:100, and 1:150) between aquaporin Z and the phospholipids, and we propose a possibility of the existence of optimal protein-lipid molar ratio to maximize water permeability. Elucidating these simulation results from a structural viewpoint suggests that there is a relationship between the permeability and changes in the hydrophobic thickness of the lipid membrane adjacent to the aquaporin as a structural parameter. The results of this study can help optimize the design of an aquaporin-lipid membrane by considering its molar ratio at an early stage of development.


Assuntos
Aquaporinas/metabolismo , Proteínas de Escherichia coli/metabolismo , Bicamadas Lipídicas/metabolismo , Fosfolipídeos/metabolismo , Purificação da Água/métodos , Água/metabolismo , Aquaporinas/química , Proteínas de Escherichia coli/química , Interações Hidrofóbicas e Hidrofílicas , Bicamadas Lipídicas/química , Modelos Químicos , Simulação de Dinâmica Molecular , Pressão Osmótica , Fosfolipídeos/química , Salinidade , Água/química
17.
Ecotoxicol Environ Saf ; 204: 110977, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32739673

RESUMO

Indirect oxidation induced by reactive free radicals, such as hydroxyl radical (HO), sulfate radical (SO4-) and carbonate radical (CO3-), plays an important or even crucial role in the degradation of micropollutants. Thus, the coadjutant degradation of phenacetin (PNT) by HO, SO4- and CO3-, as well as the synergistic effect of O2 on HO and HO2 were studied through mechanism, kinetics and toxicity evaluation. The results showed that the degradation of PNT was mainly caused by radical adduct formation (RAF) reaction (69% for Г, the same as below) and H atom transfer (HAT) reaction (31%) of HO. For the two inorganic anionic radicals, SO4- initiated PNT degradation by sequential radical addition-elimination (SRAE; 55%), HAT (28%) and single electron transfer (SET; 17%) reactions, while only by HAT reaction for CO3-. The total initial reaction rate constants of PNT by three radicals were in the order: SO4- > HO > CO3-. The kinetics of PNT degradation simulated by Kintecus program showed that UV/persulfate could degrade target compound more effectively than UV/H2O2 in ultrapure water. In the subsequent reaction of PNT with O2, HO and HO2, the formation of mono/di/tri-hydroxyl substitutions and unsaturated aldehydes/ketones/alcohols were confirmed. The results of toxicity assessment showed that the acute and chronic toxicity of most products to fish increased and to daphnia decreased, and acute toxicity to green algae decreased while chronic toxicity increased.


Assuntos
Carbonatos/toxicidade , Peróxido de Hidrogênio/toxicidade , Fenacetina/toxicidade , Sulfatos/toxicidade , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica , Animais , Carbonatos/química , Clorófitas/efeitos dos fármacos , Daphnia/efeitos dos fármacos , Peixes , Peróxido de Hidrogênio/química , Íons/química , Íons/toxicidade , Cinética , Modelos Químicos , Oxigênio/química , Fenacetina/química , Sulfatos/química , Água/química
18.
J Comput Chem ; 41(24): 2158-2161, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: covidwho-671260

RESUMO

D614G spike glycoprotein (sgp) mutation in rapidly spreading severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) is associated with enhanced fitness and higher transmissibility in new cases of COVID-19 but the underlying mechanism is unknown. Here, using atomistic simulation, a plausible mechanism has been delineated. In G614 sgp but not wild type, increased D(G)614-T859 Cα-distance within 65 ns is interpreted as S1/S2 protomer dissociation. Overall, ACE2-binding, post-fusion core, open-state and sub-optimal antibody-binding conformations were preferentially sampled by the G614 mutant, but not wild type. Furthermore, in the wild type, only one of the three sgp chains has optimal communication route between residue 614 and the receptor-binding domain (RBD); whereas, two of the three chains communicated directly in G614 mutant. These data provide evidence that D614G sgp mutant is more available for receptor binding, cellular invasion and reduced antibody interaction; thus, providing framework for enhanced fitness and higher transmissibility in D614G SARS-COV-2 mutant.


Assuntos
Betacoronavirus/metabolismo , Simulação por Computador , Infecções por Coronavirus/virologia , Modelos Químicos , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Modelos Moleculares , Mutação , Pandemias , Ligação Proteica , Conformação Proteica , Domínios Proteicos
19.
Phys Chem Chem Phys ; 22(33): 18272-18283, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: covidwho-695147

RESUMO

The COVID-19 pandemic poses a severe threat to human health with unprecedented social and economic disruption. Spike (S) glycoprotein in the SARS-CoV-2 virus is pivotal in understanding the virus anatomy, since it initiates the early contact with the ACE2 receptor in the human cell. The subunit S1 in chain A of S-protein has four structural domains: the receptor binding domain (RBD), the n-terminal domain (NTD) and two subdomains (SD1, SD2). We report details of the intra- and inter-molecular binding mechanism of RBD using density functional theory, including electronic structure, interatomic bonding and partial charge distribution. We identify five strong hydrogen bonds and analyze their roles in binding. This provides a pathway to a quantum-chemical understanding of the interaction between the S-protein and the ACE2 receptor with insights into the function of conserved features in the ACE2 receptor binding domain that could inform vaccine and drug development.


Assuntos
Betacoronavirus/química , Peptidil Dipeptidase A/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Teoria da Densidade Funcional , Humanos , Ligação de Hidrogênio , Modelos Químicos , Peptidil Dipeptidase A/química , Ligação Proteica , Domínios Proteicos , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química
20.
J Chem Phys ; 153(7): 075101, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: covidwho-726966

RESUMO

In 2020, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide and caused the coronavirus disease 2019 (COVID-19). Spike (S) glycoproteins on the viral membrane bind to ACE2 receptors on the host cell membrane and initiate fusion, and S protein is currently among the primary drug target to inhibit viral entry. The S protein can be in a receptor inaccessible (closed) or accessible (open) state based on down and up positions of its receptor-binding domain (RBD), respectively. However, conformational dynamics and the transition pathway between closed to open states remain unexplored. Here, we performed all-atom molecular dynamics (MD) simulations starting from closed and open states of the S protein trimer in the presence of explicit water and ions. MD simulations showed that RBD forms a higher number of interdomain interactions and exhibits lower mobility in its down position than its up position. MD simulations starting from intermediate conformations between the open and closed states indicated that RBD switches to the up position through a semi-open intermediate that potentially reduces the free energy barrier between the closed and open states. Free energy landscapes were constructed, and a minimum energy pathway connecting the closed and open states was proposed. Because RBD-ACE2 binding is compatible with the semi-open state, but not with the closed state of the S protein, we propose that the formation of the intermediate state is a prerequisite for the host cell recognition.


Assuntos
Betacoronavirus/química , Glicoproteína da Espícula de Coronavírus/química , Sítios de Ligação , Ligação de Hidrogênio , Modelos Químicos , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Análise de Componente Principal , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Receptores Virais/química , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica
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