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1.
Biophys Chem ; 256: 106281, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756663

RESUMO

Timely and accurate diagnosis of Alzheimer's disease (AD) remains a major challenge in the medical arena. ß-amyloid (Aß) imaging techniques such as positron emission tomography and single photon emission computed tomography require the use of an imaging probe. To date, only flutemetamol, florbetaben and florbetapir have been approved for clinical use as imaging probes. Design of imaging probes requires a detailed understanding of disease mechanism(s) and receptor-ligand interaction. In this study, molecular docking, molecular dynamics and binding free energies were used to investigate the multiple binding sites exhibited by ß-amyloid fibrils. Protein atomic models 2BEG, 5KK3, 2M4J, 2LMN, 5OQV, 2NAO, 2MVX and 2MXU (protein databank codes) were used to investigate the nature and location of binding sites and binding profiles of selected molecules with known affinities. Although amyloid fibrils are known to have multiple binding sites, we demonstrated that model 2MXU possesses one site which is druggable and can bind with common scaffolds currently being used in the imaging of amyloid fibrils. Models 2NAO, 5KK3 and 2M4J revealed that even though multiple sites may be available in some fibrils, the entire protein may not have a druggable site. Molecular dynamics revealed atomic models 2MXU and 2MVX to be the least flexible among the list. The outcomes of this investigation can be translated to assist in designing novel molecules that can be used for brain imaging in Alzheimer's disease.


Assuntos
Amiloide/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Sítios de Ligação , Bases de Dados de Proteínas , Humanos , Ligantes , Ligação Proteica , Estrutura Terciária de Proteína
2.
Biophys Chem ; 257: 106315, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31841862

RESUMO

Lipocalins are a widely distributed family of extracellular proteins typically involved in the transport of small hydrophobic molecules. To gain new insights into the molecular basis that governs ligand recognition by this ancient protein family, the binding properties of the domain-swapped dimer bovine odorant binding protein (bOBP) and its monomeric mutant bOBP121G+ were characterized using calorimetric techniques and molecular dynamics simulations. Thermal unfolding profiles revealed that the isolated bOBP subunits behave as a cooperative folding unit. In addition, bOBP and bOBP121G+ exhibited similar ligand binding properties, characterized by a non-classical hydrophobic effect signature. The energetic differences in the binding of bOBP to 1-hexen-3-ol and the physiological ligand 1-octen-3-ol were strikingly larger than those observed for the interaction of other lipocalins with congeneric ligands. MD simulations revealed that the recurrent opening of transient pores in the submicrosecond timescale allows a profuse exchange of water molecules between the protein interior and the surrounding solvent. This picture contrasts with other lipocalins whose ligand-free binding cavities are devoid of solvent molecules. Furthermore, the simulations indicated that internal water molecules solvate the protein cavity suboptimally, forming fewer hydrogen bonds and having lower density and higher potential energy than bulk water molecules. Upon ligand occupation, water molecules were displaced from the binding cavity in an amount that depended on the ligand size. Taken together, calorimetric and MD-simulation results are consistent with a significant contribution of cavity desolvation to the enthalpically-driven interaction of bOBP with its hydrophobic ligands.


Assuntos
Ligantes , Receptores Odorantes/química , Solventes/química , Animais , Sítios de Ligação , Bovinos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Estabilidade Proteica , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Termodinâmica , Água/química
3.
Biophys Chem ; 257: 106258, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31881504

RESUMO

Recent methodological progress in quantum-chemical calculations using the "embedded cluster reference interaction site model" (EC-RISM) integral equation theory is reviewed in the context of applying it as a solvation model for calculating pressure-dependent thermodynamic and spectroscopic properties of molecules immersed in water. The methodology is based on self-consistent calculations of electronic and solvation structure around dissolved molecules where pressure enters the equations via an appropriately chosen solvent response function and the pure solvent density. Besides specification of a dispersion-repulsion force field for solute-solvent interactions, the EC-RISM approach derives the electrostatic interaction contributions directly from the wave function. We further develop and apply the method to a variety of benchmark cases for which computational or experimental reference data are either available in the literature or are generated specifically for this purpose in this work. Starting with an enhancement to predict hydration free energies at non-ambient pressures, which is the basis for pressure-dependent molecular population estimation, we demonstrate the performance on the calculation of the autoionization constant of water. Spectroscopic problems are addressed by studying the biologically relevant small osmolyte TMAO (trimethylamine N-oxide). Pressure-dependent NMR shifts are predicted and compared to experiments taking into account proper computational referencing methods that extend earlier work. The experimentally observed IR blue-shifts of certain vibrational bands of TMAO as well as of the cyanide anion are reproduced by novel methodology that allows for weighing equilibrium and non-equilibrium solvent relaxation effects. Taken together, the model systems investigated allow for an assessment of the reliability of the EC-RISM approach for studying pressure-dependent biophysical processes.


Assuntos
Modelos Químicos , Espectroscopia de Ressonância Magnética , Metilaminas/síntese química , Metilaminas/química , Simulação de Dinâmica Molecular , Pressão , Teoria Quântica
4.
J Phys Chem Lett ; 11(1): 325-332, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31867970

RESUMO

Biomolecules often undergo large-scale conformational transitions when carrying out their functions. However, it is still challenging for conventional molecular dynamics simulations to provide adequate structural dynamics information to interpret associated mechanisms. Here, we present a combined elastic network model and enhanced sampling-based strategy (iterANM-IaMD) by adopting iterANM to construct initial conformation space and enhanced sampling IaMD to explore the free energy landscape along specific large-scale conformational transitions. We applied this strategy to three functionally and structurally distinct proteins (adenylate kinase, calmodulin, and p38α kinase), which undergo striking conformational change upon ligand binding. The simulation results for both free and ligand-bound proteins show qualitative and quantitative agreement with existing studies, suggesting iterANM-IaMD as an accurate and efficient tool to investigate structural dynamics involved in complicated biological processes. Our work also provides insights into the relationship between the dynamics and functionality of biomolecules.


Assuntos
Elasticidade , Simulação de Dinâmica Molecular , Proteínas/química , Conformação Proteica
5.
J Chem Phys ; 151(23): 235101, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864244

RESUMO

Association of proteins and other biopolymers is a ubiquitous process in living systems. Recent single-molecule measurements probe the dynamics of association in unprecedented detail by measuring the properties of association transition paths, i.e., short segments of molecular trajectories between the time the proteins are close enough to interact and the formation of the final complex. Interpretation of such measurements requires adequate models for describing the dynamics of experimental observables. In an effort to develop such models, here we report a simulation study of the association dynamics of two oppositely charged, disordered polymers. We mimic experimental measurements by monitoring intermonomer distances, which we treat as "experimental reaction coordinates." While the dynamics of the distance between the centers of mass of the molecules is found to be memoryless and diffusive, the dynamics of the experimental reaction coordinates displays significant memory and can be described by a generalized Langevin equation with a memory kernel. We compute the most commonly measured property of transition paths, the distribution of the transition path time, and show that, despite the non-Markovianity of the underlying dynamics, it is well approximated as one-dimensional diffusion in the potential of mean force provided that an apparent value of the diffusion coefficient is used. This apparent value is intermediate between the slow (low frequency) and fast (high frequency) limits of the memory kernel. We have further studied how the mean transition path time depends on the ionic strength and found only weak dependence despite strong electrostatic attraction between the polymers.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Simulação de Dinâmica Molecular , Sítios de Ligação
6.
Phys Chem Chem Phys ; 21(44): 24269-24285, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31670327

RESUMO

An enormous population worldwide is presently confronted with debilitating neurodegenerative diseases. The etiology of the disease is connected to protein aggregation and the events involved therein. Thus, a complete understanding of an inhibitor at different stages in the process is imperative for the formulation of a drug molecule. This review presents a detailed summary of the current status of different cosolvents. It further develops how the complex aggregation pathway can be simplified into three steps common to all proteins and the way computer simulations can be exploited to gain insights into the ways by which known inhibitors can affect all these stages. Computation of theoretical parameters in this regard and their correlation with experimental techniques is accentuated. In addition to providing an outline of the scope of different additives, this review showcases the way by which the problem of analyzing an effect of an additive can be addressed effectively via MD simulations.


Assuntos
Proteínas/química , Antioxidantes/química , Antioxidantes/farmacologia , Desenho de Drogas , Humanos , Simulação de Dinâmica Molecular , Monossacarídeos/química , Monossacarídeos/farmacologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Agregados Proteicos/efeitos dos fármacos , Proteínas/metabolismo
7.
Phys Chem Chem Phys ; 21(45): 25276-25289, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701109

RESUMO

As a member of the bromodomain and extra terminal domain (BET) protein family, bromodomain-containing protein 4 (BRD4) is an epigenetic reader and can recognize acetylated lysine residues in histones. BRD4 has been regarded as an essential drug target for cancers, inflammatory diseases and acute heart failure, and therefore the discovery of potent BRD4 inhibitors with novel scaffolds is highly desirable. In this study, the crystalline water molecules in BRD4 involved in ligand binding were analyzed first, and the simulation results suggest that several conserved crystalline water molecules are quite essential to keep the stability of the crystalline water network and therefore they need to be reserved in structure-based drug design. Then, a docking-based virtual screening workflow with the consideration of the conserved crystalline water network in the binding pocket was utilized to identify the potential inhibitors of BRD4. The in vitro fluorescence resonance energy transfer (HTRF) binding assay illustrates that 4 hits have good inhibitory activity against BRD4 in the micromolar regime, including three compounds with IC50 values below 5 µM and one below 1 µM (0.37 µM). The structural analysis demonstrates that three active compounds possess novel scaffolds. Moreover, the interaction patterns between the hits and BRD4 were characterized by molecular dynamics simulations and binding free energy calculations, and then several suggestions for the further optimization of these hits were proposed.


Assuntos
Simulação de Acoplamento Molecular , Proteínas Nucleares/química , Fatores de Transcrição/química , Água/química , Proteínas de Ciclo Celular , Cristalização , Transferência Ressonante de Energia de Fluorescência , Humanos , Simulação de Dinâmica Molecular , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores
8.
J Chem Phys ; 151(18): 185101, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31731860

RESUMO

The function of critical biological materials, such as proteins, is intrinsically tied to their structure, and this structure is in turn heavily dependent on the properties of the solvent, most commonly water or dilute aqueous solutions. As water is known to exhibit anomalous properties, especially at supercooled temperatures, it is natural to ask how these properties might impact the thermodynamics of protein folding. To investigate this question, we use molecular simulation to explore the behavior of a model miniprotein, Trp-cage, as low as 70 K below the freezing point of the solvent at ambient pressure. Surprisingly, we find that while the expected cold denaturation of the protein is observed at moderate supercooling, further cooling to more than 55 K below the freezing point leads to cold refolding of the protein. Structural and hydrogen bonding analysis suggests that this refolding is driven by the desolvation of the protein's hydrophobic core, likely related to the pronounced decrease in density at this temperature. Beyond their intrinsic fundamental interest, these results have implications for cryomicroscopy and cryopreservation, where biological materials are often transiently subjected to these extreme conditions.


Assuntos
Simulação de Dinâmica Molecular , Redobramento de Proteína , Proteínas/química , Temperatura Ambiente
9.
J Chem Phys ; 151(19): 195102, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31757139

RESUMO

Here, we investigate the unfolding behavior of a streptomycin-binding ribonucleic acid (RNA) aptamer under application of force in shear geometry. Using Langevin out-of-equilibrium simulations to emulate the single-molecule force spectroscopy (SMFS) experiment, we were able to understand the hierarchical unfolding process that occurs in the RNA molecule under application of stretching force and the influence of streptomycin modifying this unfolding. Subsequently, the application of the Jarzynski equality to the force profiles obtained in the pulling simulations shows that the free energies for individual systems and the difference of unfolding free energy upon streptomycin binding to the RNA free aptamer are in fair agreement with the experimental values, obtained through SMFS by Nick et al. [J. Phys. Chem. B 120, 6479 (2016)].


Assuntos
Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Microscopia de Força Atômica , Simulação de Dinâmica Molecular , Estreptomicina/metabolismo , Conformação de Ácido Nucleico , Ligação Proteica , Termodinâmica
10.
J Phys Chem Lett ; 10(22): 7200-7207, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31693374

RESUMO

DNA compaction is essential to ensure the packaging of the genetic material in living cells and also plays a key role in the epigenetic regulation of gene expression. In both humans and bacteria, DNA packaging is achieved by specific well-conserved proteins. Here, by means of all-atom molecular dynamics simulations, including the determination of relevant free-energy profiles, we rationalize the molecular bases for this remarkable process in bacteria, illustrating the crucial role played by positively charged amino acids of a small histone-like protein. We also present compelling evidence that this histone-like protein alone can induce strong bending of a DNA duplex around its core domain, a process that requires overcoming a major free-energy barrier.


Assuntos
Proteínas de Bactérias/química , Borrelia burgdorferi/química , Empacotamento do DNA , DNA Bacteriano/química , Histonas/química , Simulação de Dinâmica Molecular , Modelos Moleculares
11.
Sheng Wu Gong Cheng Xue Bao ; 35(10): 1819-1828, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31668031

RESUMO

We review major computational chemistry techniques applied in industrial enzyme studies, especially approaches intended for guiding enzyme engineering. These include molecular mechanics force field and molecular dynamics simulation, quantum mechanical and combined quantum mechanical/molecular mechanical approaches, electrostatic continuum models, molecular docking, etc. These approaches are essentially introduced from the following two angles for viewing: one is about the methods themselves, including the basic concepts, the primary computational results, and potential advantages and limitations; the other is about obtaining valuable information from the respective calculations to guide the design of mutants and mutant libraries.


Assuntos
Enzimas/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Engenharia de Proteínas , Teoria Quântica , Enzimas/química , Enzimas/genética , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Eletricidade Estática
12.
Adv Exp Med Biol ; 1163: 187-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707705

RESUMO

Computational studies of allosteric interactions have witnessed a recent renaissance fueled by the growing interest in modeling of the complex molecular assemblies and biological networks. Allosteric interactions in protein structures allow for molecular communication in signal transduction networks. In this chapter, we discuss recent developments in understanding of allosteric mechanisms and interactions of protein systems, particularly in the context of structural, functional, and computational studies of allosteric inhibitors and activators. Computational and experimental approaches and advances in understanding allosteric regulatory mechanisms are reviewed to provide a systematic and critical view of the current progress in the development of allosteric modulators and highlight most challenging questions in the field. The abundance and diversity of genetic, structural, and biochemical data underlies the complexity of mechanisms by which targeted and personalized drugs can combat mutational profiles in protein kinases. Structural and computational studies of protein kinases have generated in recent decade significant insights that allowed leveraging knowledge about conformational diversity and allosteric regulation of protein kinases in the design and discovery of novel kinase drugs. We discuss recent developments in understanding multilayered allosteric regulatory machinery of protein kinases and provide a systematic view of the current state in understanding molecular basis of allostery mediated by kinase inhibitors and activators. In conclusion, we highlight the current status and future prospects of computational biology approaches in bridging the basic science of protein kinases with the discovery of anticancer therapies.


Assuntos
Regulação Alostérica , Biologia Computacional , Mapas de Interação de Proteínas , Inibidores de Proteínas Quinases , Proteínas Quinases , Transdução de Sinais , Regulação Alostérica/efeitos dos fármacos , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
J Chem Phys ; 151(16): 164902, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31675856

RESUMO

Most of the anticancer drugs bind to double-stranded DNA (dsDNA) by intercalative-binding mode. Although experimental studies have become available recently, a molecular-level understanding of the interactions between the drug and dsDNA that lead to the stability of the intercalated drug is lacking. Of particular interest are the modifications of the mechanical properties of dsDNA observed in experiments. The latter could affect many biological functions, such as DNA transcription and replication. Here, we probe, via all-atom molecular dynamics (MD) simulations, the change in the mechanical properties of intercalated drug-DNA complexes for two intercalators, daunomycin and ethidium. We find that, upon drug intercalation, the stretch modulus of DNA increases significantly, whereas its persistence length and bending modulus decrease. Steered MD simulations reveal that it requires higher forces to stretch the intercalated dsDNA complexes than the normal dsDNA. Adopting various pulling protocols to study force-induced DNA melting, we find that the dissociation of dsDNA becomes difficult in the presence of intercalators. The results obtained here provide a plausible mechanism of function of the anticancer drugs, i.e., via altering the mechanical properties of DNA. We also discuss long-time consequences of using these drugs, which require further in vivo investigations.


Assuntos
Antineoplásicos/química , DNA/química , Substâncias Intercalantes/química , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico
15.
J Chem Phys ; 151(16): 164105, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31675872

RESUMO

The kinetics of bimolecular reactions in solution depends, among other factors, on intermolecular forces such as steric repulsion or electrostatic interaction. Microscopically, a pair of molecules first has to meet by diffusion before the reaction can take place. In this work, we establish an extension of Doi's volume reaction model to molecules interacting via pair potentials, which is a key ingredient for interacting-particle-based reaction-diffusion (iPRD) simulations. As a central result, we relate model parameters and macroscopic reaction rate constants in this situation. We solve the corresponding reaction-diffusion equation in the steady state and derive semi-analytical expressions for the reaction rate constant and the local concentration profiles. Our results apply to the full spectrum from well-mixed to diffusion-limited kinetics. For limiting cases, we give explicit formulas, and we provide a computationally inexpensive numerical scheme for the general case, including the intermediate, diffusion-influenced regime. The obtained rate constants decompose uniquely into encounter and formation rates, and we discuss the effect of the potential on both subprocesses, exemplified for a soft harmonic repulsion and a Lennard-Jones potential. The analysis is complemented by extensive stochastic iPRD simulations, and we find excellent agreement with the theoretical predictions.


Assuntos
Modelos Químicos , Simulação de Dinâmica Molecular , Difusão , Cinética
16.
Phys Chem Chem Phys ; 21(46): 25707-25719, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31720635

RESUMO

To prevent irreversible damage caused by an excess of incident light, the photosynthetic machinery of many cyanobacteria uniquely utilizes the water-soluble orange carotenoid protein (OCP) containing a single keto-carotenoid molecule. This molecule is non-covalently embedded into the two OCP domains which are interconnected by a flexible linker. The phenomenon of OCP photoactivation, causing significant changes in carotenoid absorption in the orange and red form of OCP, is currently being thoroughly studied. Numerous additional spectral forms of natural and synthetic OCP-like proteins have been unearthed. The optical properties of carotenoids are strongly determined by the interaction of their electronic states with vibrational modes, the surrounding protein matrix, and the solvent. In this work, the effects of the pigment-protein interaction and vibrational relaxation in OCP were studied by computational simulation of linear absorption. Taking into account Raman spectroscopy data and applying the multimode Brownian oscillator model as well as the cumulant expansion technique, we have calculated a set of characteristic microparameters sufficient to demarcate different carotenoid states in OCP forms, using the model carotenoids spheroidene and spheroidenone in methanol/acetone solution as benchmarks. The most crucial microparameters, which determine the effect of solvent and protein environment, are the Huang-Rhys factors and the frequencies of C[double bond, length as m-dash]C and C-C stretching modes, the low-frequency mode and the FWHM due to inhomogeneous line broadening. Considering the difference of linear absorption between spheroidene and spheroidenone, which remarkably resembles the photoinduced changes of OCP absorption, and applying quantum chemical calculations, we discuss structural and functional determinants of carotenoid binding proteins.


Assuntos
Proteínas de Bactérias/química , Carotenoides/química , Simulação de Dinâmica Molecular , Teoria Quântica , Água/química , Estrutura Molecular , Solubilidade
17.
Phys Chem Chem Phys ; 21(46): 25584-25596, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31720639

RESUMO

The conjugation of polyethylene glycol (PEG) to proteins, known as PEGylation, has increasingly been employed to expand the efficacy of therapeutic drugs. Recently, research has emphasized the effect of the conjugation site on protein-polymer interactions. In this study, we performed atomistic molecular dynamics (MD) simulations of lysine 116 PEGylated bovine serum albumin (BSA) to illustrate how conjugation near a hydrophobic pocket affects the conjugate's dynamics and observed altered low mode vibrations in the protein. MD simulations were performed for a total of 1.5 µs for each PEG chain molecular mass from 2 to 20 kDa. Analysis of preferential PEG-BSA interactions showed that polymer behavior was also affected as proximity to the attractive protein surface patches promoted interactions in small (2 kDa) PEG chains, while the confined environment of the conjugation site reduced the expected BSA surface coverage when the polymer molecular mass increased to 10 kDa. This thorough analysis of PEG-BSA interactions and polymer dynamics increases the molecular understanding of site-specific PEGylation and enhances the use of protein-polymer conjugates as therapeutics.


Assuntos
Polietilenoglicóis/química , Soroalbumina Bovina/química , Animais , Bovinos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular
18.
Phys Chem Chem Phys ; 21(42): 23338-23345, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31617504

RESUMO

Nature exploits different strategies for enhancing the catalytic activity of enzymes, often resorting to producing beneficial mutations. The case of post-translational proline hydroxylation mutation in the active site of polysaccharide deacetylase (PDA) Bc1960 from Bacillus cereus is an interesting example of how small chemical modifications can cause significant improvements in enzymatic activity. In the present study the deacetylation mechanism promoted by both OH-proline (2Hyp) and standard proline (Pro) containing PDA is investigated using density functional theory. Although the mechanism presented for the two examined enzymes is in agreement with protease catalysis in metalloenzymes, the analysis along the potential energy surface (PES) reveals that the intermediate and product benefit energetically from the presence of the hydroxyl group on the proline. Our calculations provide evidence that for PDA-2Hyp, the hydrogen bond network established by the -OH group on the Cα of the proline with its closest neighbors stabilizes the transition states and, consequently, the reaction takes advantage of this. These results further contribute towards explaining the different catalytic activity experimentally observed for the polysaccharide deacetylase enzymes.


Assuntos
Amidoidrolases/metabolismo , Hidroxiprolina/metabolismo , Amidoidrolases/química , Bacillus cereus/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Biocatálise , Ligações de Hidrogênio , Hidroxiprolina/química , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína , Termodinâmica
19.
Phys Chem Chem Phys ; 21(42): 23501-23513, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31617551

RESUMO

YIV-906 (formally PHY906, KD018) is a four-herb formulation that is currently being developed to improve the therapeutic index and ameliorate the side effects of many chemotherapeutic drugs including sorafenib, irinotecan, and capecitabine. However, as a promising anti-cancer adjuvant, the molecular mechanism of action of YIV-906 remains unrevealed due to its multi-component and multi-target features. Since YIV-906 has been shown to induce apoptosis and autophagy in cancer cells through modulating the negative regulators of ERK1/2, namely DUSPs, it is of great interest to elucidate the key components that cause the therapeutic effect of YIV-906. In this work, we investigated the mechanism of YIV-906 inhibiting DUSPs, using a broad spectrum of molecular modelling techniques, including molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. In total, MD simulations and binding free energy calculations were performed for 99 DUSP-ligand complexes. We found that some herbal components or their metabolites could inhibit DUSPs. Based on the docking scores and binding free energies, the sulfation and glucuronidation metabolites of the S ingredient in YIV-906 play a leading role in inhibiting DUSPs, although several original herbal chemicals with carboxyl groups from the P and Z ingredients also make contributions to this inhibitory effect. It is not a surprise that the electrostatic interaction plays the dominant role in the ligand binding process, given the fact that several charged residues reside in the binding pockets of DUSPs. Our MD simulation results demonstrate that the sulfate moieties and carboxyl moieties of the advantageous ligands from YIV-906 can occupy the enzymes' catalytic sites, mimicking the endogenous phosphate substrates of DUSPs. As such, the ligand binding can inhibit the association of DUSPs and ERK1/2, which in turn reduces the dephosphorylation of ERK1/2 and causes cell cycle arrest in the tumor. Our modelling study provides useful insights into the rational design of highly potent anti-cancer drugs targeting DUSPs. Finally, we have demonstrated that multi-scale molecular modelling techniques are able to elucidate molecular mechanisms involving complex molecular systems.


Assuntos
Antineoplásicos Fitogênicos/química , Medicamentos de Ervas Chinesas/química , Antineoplásicos Fitogênicos/metabolismo , Sítios de Ligação , Domínio Catalítico , Medicamentos de Ervas Chinesas/metabolismo , Fosfatases de Especificidade Dupla/antagonistas & inibidores , Fosfatases de Especificidade Dupla/metabolismo , Humanos , Ligantes , Proteína Quinase 3 Ativada por Mitógeno/química , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Termodinâmica
20.
Phys Chem Chem Phys ; 21(42): 23514-23520, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31617554

RESUMO

Inherent molecular fluctuations are known to have a significant influence on the charge transport properties of biomolecules like DNA, PNA and proteins. In this work, we show ways to control these fluctuations and further demonstrate their use to enhance the conductance of two widely studied molecular wires, namely dsDNA (DNA) and G4 Quadruplex (G4-Quad). We quantify the molecular fluctuation in terms of the root mean square deviation (RMSD) of the molecule. In the case of DNA, we use temperature to control the fluctuations, while in the case of G4-Quad the fluctuations are tuned by the ions inside the pore. The electronic coupling between the bases of dsDNA and G4-Quad, which measures the conductance of these molecular wires, shows a non-monotonic behaviour with the increase in fluctuation. We find values of fluctuation which give rise to maximum electronic coupling and hence high conductivity for both the cases. In the case of DNA, these optimal fluctuations (∼2.5 Å) are achieved at a temperature of 210 K, which gives rise to an electronic coupling of 0.135 eV between the DNA bases. The optimal fluctuations in G4-Quad are achieved (∼7 Å) in a 4 base pair long system with 2 Na+ ions inside the pore, giving rise to an electronic coupling of 0.09 eV.


Assuntos
DNA/química , Condutividade Elétrica , Quadruplex G , Simulação de Dinâmica Molecular , Ácidos Nucleicos Peptídicos/química , Proteínas/química , Teoria Quântica , Temperatura Ambiente
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