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Given the prevalence of the malignant weed Chinese Sprangletop (Leptochloa chinensis (L.) Nees) in rice fields, the development of novel herbicides against this weed has aroused wide interest. Here, we report a novel diphenyl ether-pyrimidine hybrid, DEP-5, serving as a systematic pre/postemergence herbicide candidate for broad-spectrum weed control in rice fields, specifically for L. chinensis. Notably, DEP-5 exhibits over 80% herbicidal activity against the resistant biotypes even at 37.5 g a.i./ha under greenhouse conditions and has complete control of L. chinensis at 150 g a.i./ha in the rice fields. We uncover that DEP-5 acts as a noncompetitive inhibitor of acetohydroxyacid synthase (AHAS) with an inhibition constant (Ki) of 39.4 µM. We propose that DEP-5 binds to AHAS in two hydrophobic-driven binding modes that differ from commercial AHAS inhibitors. Overall, these findings demonstrate that DEP-5 has great potential to be developed into a herbicide for L. chinensis control and inspire fresh concepts for novel AHAS-inhibiting herbicide design.
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Acetolactato Sintasa , Herbicidas , Oryza , Proteínas de Plantas , Malezas , Poaceae , Control de Malezas , Herbicidas/farmacología , Herbicidas/química , Oryza/química , Malezas/efectos de los fármacos , Malezas/enzimología , Acetolactato Sintasa/metabolismo , Acetolactato Sintasa/antagonistas & inhibidores , Acetolactato Sintasa/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/antagonistas & inhibidores , Poaceae/química , Poaceae/enzimología , Poaceae/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Pirimidinas/farmacología , Cinética , Éteres Fenílicos/farmacología , Éteres Fenílicos/químicaRESUMEN
Herbicides are useful tools for managing weeds and promoting food production and sustainable agriculture. In this study, we report on the development of a novel class of lipophilic pyrimidine-biphenyl (PMB) herbicides. Firstly, three PMBs, Ia, IIa, and IIIa, were rationally designed via a scaffold hopping strategy and were determined to inhibit acetohydroxyacid synthase (AHAS). Computational simulation was carried out to investigate the molecular basis for the efficiency of PMBs against AHAS. With a rational binding mode, and the highest in vitro as well as in vivo potency, Ia was identified as a preferable hit. Furthermore, these integrated analyses guided the design of eighteen new PMBs, which were synthesized via a one-step Suzuki-Miyaura cross-coupling reaction. These new PMBs, Iba-ic, were more effective in post-emergence control of grass weeds compared with Ia. Interestingly, six of the PMBs displayed 98-100% inhibition in the control of grass weeds at 750 g ai/ha. Remarkably, Ica exhibited ≥ 80% control against grass weeds at 187.5 g ai/ha. Overall, our comprehensive and systematic investigation revealed that a structurally distinct class of lipophilic PMB herbicides, which pair excellent herbicidal activities with new interactions with AHAS, represent a noteworthy development in the pursuit of sustainable weed control solutions.
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Herbicidas , Pirimidinas , Herbicidas/química , Herbicidas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Acetolactato Sintasa/antagonistas & inhibidores , Acetolactato Sintasa/metabolismo , Acetolactato Sintasa/química , Compuestos de Bifenilo/química , Compuestos de Bifenilo/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Malezas/efectos de los fármacos , Relación Estructura-Actividad , Estructura MolecularRESUMEN
BACKGROUND: Carbon nano sol (CNS) can markedly affect the plant growth and development. However, few systematic analyses have been conducted on the underlying regulatory mechanisms in plants, including tobacco (Nicotiana tabacum L.). RESULTS: Integrated analyses of phenome, ionome, transcriptome, and metabolome were performed in this study to elucidate the physiological and molecular mechanisms underlying the CNS-promoting growth of tobacco plants. We found that 0.3% CNS, facilitating the shoot and root growth of tobacco plants, significantly increased shoot potassium concentrations. Antioxidant, metabolite, and phytohormone profiles showed that 0.3% CNS obviously reduced reactive oxygen species production and increased antioxidant enzyme activity and auxin accumulation. Comparative transcriptomics revealed that the GO and KEGG terms involving responses to oxidative stress, DNA binding, and photosynthesis were highly enriched in response to exogenous CNS application. Differential expression profiling showed that NtNPF7.3/NtNRT1.5, potentially involved in potassium/auxin transport, was significantly upregulated under the 0.3% CNS treatment. High-resolution metabolic fingerprints showed that 141 and 163 metabolites, some of which were proposed as growth regulators, were differentially accumulated in the roots and shoots under the 0.3% CNS treatment, respectively. CONCLUSIONS: Taken together, this study revealed the physiological and molecular mechanism underlying CNS-mediated growth promotion in tobacco plants, and these findings provide potential support for improving plant growth through the use of CNS.
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Carbono , Metabolómica , Nicotiana , Reguladores del Crecimiento de las Plantas , Transcriptoma , Nicotiana/genética , Nicotiana/metabolismo , Nicotiana/crecimiento & desarrollo , Carbono/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Perfilación de la Expresión Génica , Metaboloma , Raíces de Plantas/metabolismo , Raíces de Plantas/crecimiento & desarrollo , Raíces de Plantas/genética , Brotes de la Planta/metabolismo , Brotes de la Planta/crecimiento & desarrollo , Brotes de la Planta/genéticaRESUMEN
Oriental tobacco budworm (Helicoverpa assulta) and cotton bollworm (Helicoverpa armigera) are two closely related species within the genus Helicoverpa. They have similar appearances and consistent damage patterns, often leading to confusion. However, the cotton bollworm is a typical polyphagous insect, while the oriental tobacco budworm belongs to the oligophagous insects. In this study, we used Nanopore, PacBio, and Illumina platforms to sequence the genome of H. assulta and used Hifiasm to create a haplotype-resolved draft genome. The Hi-C technique helped anchor 33 primary contigs to 32 chromosomes, including two sex chromosomes, Z and W. The final primary haploid genome assembly was approximately 415.19 Mb in length. BUSCO analysis revealed a high degree of completeness, with 99.0% gene coverage in this genome assembly. The repeat sequences constituted 38.39% of the genome assembly, and we annotated 17093 protein-coding genes. The high-quality genome assembly of the oriental tobacco budworm serves as a valuable genetic resource that enhances our comprehension of how they select hosts in a complex odour environment. It will also aid in developing an effective control policy.
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Genoma de los Insectos , Haplotipos , Mariposas Nocturnas , Animales , Mariposas Nocturnas/genética , Cromosomas de Insectos , Helicoverpa armigeraRESUMEN
Tobacco plants (Nicotiana tabacum L.) exhibit considerable potential for phytoremediation of soil cadmium (Cd) pollutants, owing to their substantial biomass and efficient metal accumulation capabilities. The reduction of Cd accumulation in tobacco holds promise for minimizing Cd intake in individuals exposed to cigar smoking. NRAMP transporters are pivotal in the processes of Cd accumulation and resistance in plants; however, limited research has explored the functions of NRAMPs in tobacco plants. In this investigation, we focused on NtNRAMP6c, one of the three homologs of NRAMP6 in tobacco. We observed a robust induction of NtNRAMP6c expression in response to both Cd toxicity and iron (Fe) deficiency, with the highest expression levels detected in the roots. Subsequent subcellular localization and heterologous expression analyses disclosed that NtNRAMP6c functions as a plasma membrane-localized Cd transporter. Moreover, its overexpression significantly heightened the sensitivity of yeast cells to Cd toxicity. Through CRISPR-Cas9-mediated knockout of NtNRAMP6c, we achieved a reduction in Cd accumulation and an enhancement in Cd resistance in tobacco plants. Comparative transcriptomic analysis unveiled substantial alterations in the transcriptional profiles of genes associated with metal ion transport, photosynthesis, and macromolecule catabolism upon NtNRAMP6c knockout. Furthermore, our study employed plant metabolomics and rhizosphere metagenomics to demonstrate that NtNRAMP6c knockout led to changes in phytohormone homeostasis, as well as shifts in the composition and abundance of microbial communities. These findings bear significant biological implications for the utilization of tobacco in phytoremediation strategies targeting Cd pollutants in contaminated soils, and concurrently, in mitigating Cd accumulation in tobacco production destined for cigar consumption.
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Contaminantes Ambientales , Contaminantes del Suelo , Humanos , Cadmio/metabolismo , Nicotiana/genética , Hierro/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Contaminantes Ambientales/análisis , Raíces de Plantas/metabolismo , Contaminantes del Suelo/análisisRESUMEN
Crystalline materials are often considered to have rigid periodic lattices, while soft materials are associated with flexibility and nonperiodicity. The continuous evolution of metal-organic frameworks (MOFs) has erased the boundaries between these two distinct conceptions. Flexibility, disorder, and defects have been found to be abundant in MOF materials with imperfect crystallinity, and their intricate interplay is poorly understood because of the limited strategies for characterizing disordered structures. Here, we apply advanced nuclear magnetic resonance spectroscopy to elucidate the mesoscale structures in a defective MOF with a semicrystalline lattice. We show that engineered defects can tune the degree of lattice flexibility by combining both ordered and disordered compartments. The one-dimensional alignment of correlated defects is the key for the reversible topological transition. The unique matrix is featured with both rigid framework of nanoporosity and flexible linkage of high swellability.
RESUMEN
The mutant KRAS was considered as an "undruggable" target for decades, especially KRASG12D. It is a great challenge to develop the inhibitors for KRASG12D which lacks the thiol group for covalently binding ligands. The discovery of MRTX1133 solved the dilemma. Interestingly, MRTX1133 can bind to both the inactive and active states of KRASG12D. The binding mechanism of MRTX1133 with KRASG12D, especially how MRTX1133 could bind the active state KRASG12D without triggering the active function of KRASG12D, has not been fully understood. Here, we used a combination of all-atom molecular dynamics simulations and Markov state model (MSM) to understand the inhibition mechanism of MRTX1133 and its analogs. The stationary probabilities derived from MSM show that MRTX1133 and its analogs can stabilize the inactive or active states of KRASG12D into different conformations. More remarkably, by scrutinizing the conformational differences, MRTX1133 and its analogs were hydrogen bonded to Gly60 to stabilize the switch II region and left switch I region in a dynamically inactive conformation, thus achieving an inhibitory effect. Our simulation and analysis provide detailed inhibition mechanism of KRASG12D induced by MRTX1133 and its analogs. This study will provide guidance for future design of novel small molecule inhibitors of KRASG12D.
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Simulación de Dinámica Molecular , Proteínas Proto-Oncogénicas p21(ras) , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Fúngicas , Compuestos de SulfhidriloRESUMEN
G protein-coupled receptors (GPCRs) are membrane proteins constituting the largest family of drug targets. The activated GPCR binds either the heterotrimeric G proteins or arrestin through its activation cycle. Water molecules have been reported to play a role in GPCR activation. Nevertheless, reported studies are focused on the hydrophobic helical bundle region. How water molecules function in GPCR bound either G protein or arrestin is rarely studied. To address this issue, we carried out computational studies on water molecules in both GPCR/G protein complexes and GPCR/arrestin complexes. Using inhomogeneous fluid theory (IFT), we locate all possible hydration sites in GPCRs binding either to G protein or arrestin. We observe that the number of water molecules on the interaction surface between GPCRs and signal proteins are correlated with the insertion depths of the α5-helix from G-protein or "finger loop" from arrestin in GPCRs. In three out of the four simulation pairs, the interfaces of Rhodopsin, M2R and NTSR1 in the G protein-associated systems show more water-mediated hydrogen-bond networks when compared to these in arrestin-associated systems. This reflects that more functionally relevant water molecules may probably be attracted in G protein-associated structures than that in arrestin-associated structures. Moreover, we find the water-mediated interaction networks throughout the NPxxY region and the orthosteric pocket, which may be a key for GPCR activation. Reported studies show that non-biased agonist, which can trigger both GPCR-G protein and GPCR-arrestin activation signal, can result in pharmacologically toxicities. Our comprehensive studies of the hydration sites in GPCR/G protein complexes and GPCR/arrestin complexes may provide important insights in the design of G-protein biased agonists.
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Arrestina , Agua , Arrestina/química , Arrestina/metabolismo , Agua/metabolismo , Receptores Acoplados a Proteínas G/química , Proteínas de Unión al GTP/metabolismo , Rodopsina/química , Rodopsina/metabolismoRESUMEN
Robust protein-nanomaterial surface analysis is important, but also a challenge. Thrombin plays an important role in the coagulant activity of protein corona mediated by Ca2+ ion exchanged zeolites. However, the mechanism for this modulation remains unresolved. In this study, we proposed a combined computational and experimental approach to determine the adsorbed sites and orientations of thrombin binding to Ca2+ -exchanged LTA-type (CaA) zeolite. Specifically, fourteen ensembles of simulated annealing molecular dynamics (SAMD) simulations and experimental surface residues microenvironment analysis were used to reduce the starting orientations needed for further molecular dynamics (MD) simulations. The combined MD simulations and procoagulant activity characterization also reveal the consequent corresponding deactivation of thrombin on CaA zeolite. It is mainly caused by two aspects: (1) the secondary structure of thrombin can change after its adsorption on the CaA zeolite. (2) The positively charged area of thrombin mediates the preferential interaction between thrombin and CaA zeolite. Some thrombin substrate sites are thus blocked by zeolite after its adsorption. This study not only provides a promising method for characterizing the protein-nanoparticle interaction, but also gives an insight into the design and application of zeolite with high procoagulant activity.
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Zeolitas , Adsorción , Zeolitas/química , TrombinaRESUMEN
The defects in metal-organic frameworks (MOFs) can dramatically alter their pore structure and chemical properties. However, it has been a great challenge to characterize the molecular structure of defects, especially when the defects are distributed irregularly in the lattice. In this work, we applied a characterization strategy based on solid-state nuclear magnetic resonance (NMR) to assess the chemistry of defects. This strategy takes advantage of the coordination-sensitive phosphorus probe molecules, e.g., trimethylphosphine (TMP) and trimethylphosphine oxide (TMPO), that can distinguish the subtle differences in the acidity of defects. A variety of local chemical environments have been identified in defective and ideal MOF lattices. The geometric dimension of defects can also be evaluated by using the homologs of probe molecules with different sizes. In addition, our method provides a reliable way to quantify the density of defect sites, which comes together with the molecular details of local pore environments. The comprehensive solid-state NMR strategy can be of great value for a better understanding of MOF structures and for guiding the design of MOFs with desired catalytic or adsorption properties.
RESUMEN
Aromatic aldehydes find extensive applications in food, perfume, pharmaceutical, and chemical industries. However, a limited natural enzyme selectivity has become the bottleneck of bioconversion of aromatic aldehydes from natural phenylpropanoid acids. Here, based on the original structure of feruloyl-coenzyme A (CoA) synthetase (FCS) from Streptomyces sp. V-1, we engineered five substrate-binding domains to match specific phenylpropanoid acids. FcsCIAE407A/K483L, FcsMAE407R/I481R/K483R, FcsHAE407K/I481K/K483I, FcsCAE407R/I481R/K483T, and FcsFAE407R/I481K/K483R showed 9.96-, 10.58-, 4.25-, 6.49-, and 8.71-fold enhanced catalytic efficiency for degrading CoA thioesters of cinnamic acid, 4-methoxycinnamic acid, 4-hydroxycinnamic acid, caffeic acid, and ferulic acid, respectively. Molecular dynamics simulation illustrated that novel substrate-binding domains formed strong interaction forces with substrates' methoxy/hydroxyl group and provided hydrophobic/alkaline catalytic surfaces. Five recombinant E. coli with FCS mutants were constructed with the maximum benzaldehyde, p-anisaldehyde, p-hydroxybenzaldehyde, protocatechualdehyde, and vanillin productivity of 6.2 ± 0.3, 5.1 ± 0.23, 4.1 ± 0.25, 7.1 ± 0.3, and 8.7 ± 0.2 mM/h, respectively. Hence, our study provided novel and efficient enzymes for the bioconversion of phenylpropanoid acids into aromatic aldehydes.
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Enoil-CoA Hidratasa , Escherichia coli , Acilcoenzima A , Aldehídos , Ácidos Cumáricos/química , Enoil-CoA Hidratasa/química , Escherichia coli/genéticaRESUMEN
HYPOTHESIS: Factor Va (FXa) and Xa (FVa) can assemble on the phosphatidylserine (PS) membrane (of platelet) to form prothrombinase complex and contribute to blood clotting. Very recently, we discovered that Ca-zeoliteacts as a type of reinforced activated inorganic platelet to enable assembly of prothrombinase complex and display an unusual zymogen (prothrombin) activation pattern. Inspired but not constrained by nature, it is of great interest to understand how FVa and FXa assembly on the inorganic surface (e.g., zeolites) and perform their biocatalytic function. EXPERIMENTS: Given the important role of FVa C1-C2 domains in the assembly and activity of the prothrombinase complex, in this work, molecular dynamics simulations were performed to investigate the binding details of FVa A3-C1-C2 domains on the PS membranes and Ca2+-LTA-type (CaA) zeolite surface. FINDINGS: We found that different from the natural PS membrane, FVa light chain repeatedly exhibits a strong C2 domain anchoring interaction on the CaA zeolite. It mainly arises from the porous surface structure of CaA zeolite and local highly dense solvation water clusters on the CaA zeolite surface restrict the movement of some lysine residues on the C2 domain. The anchoring interaction can be suppressed by reducing the surface negative charge density, so that FVa light chain can change from single-foot (only C2 domain) to double-foot (both C1-C2 domain) adsorption states on the zeolite surface. This double-foot adsorption state is similar to natural PS membrane systems, which may make FVa have higher cofactor activity.
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Factor Va , Zeolitas , Sitios de Unión , Factor Va/metabolismo , Simulación de Dinámica Molecular , Unión Proteica , Protrombina/metabolismoRESUMEN
Activatable cell-penetrating peptides (ACPPs) are known to be able to decrease the cytotoxicity of cell-penetrating peptide (CPP)-based drug delivery systems. Furthermore, they can improve the targeting of CPPs when specifically recognized and hydrolyzed by characteristic proteases. A comprehensive and profound understanding of the recognition and hydrolysis process will provide a better design of the ACPP-based drug delivery system. Previous studies have clearly described how ACPPs are recognized and bound by MMPs. However, the hydrolysis mechanism of ACPPs is still unsolved. This work focuses on a proteinase-sensitive cleavable linker of ACPPs (PLGLAG), the key structure for recognition and hydrolysis, trying to determine the mechanism by which MMP-9 hydrolyzes its substrate PLGLAG. The quantum mechanics/molecular mechanics (QM/MM) calculations herein show that MMP-9 proteolysis is a water-mediated four-step reaction. More specifically, it consists of (i) nucleophilic attack, (ii) hydrogen-bond rearrangement, (iii) proton transfer, and finally (iv) amide bond rupture. Considering the reversibility of multistep reaction, the second step (i.e., hydrogen-bond rearrangement) has the highest barrier and is the rate-limiting step in the hydrolysis of PLGLAG. The possible design and improvement of the key P1 and P1' sites are also explored through mutations. The present results indicate that, while the mutations affect the reaction energy barriers and the rate-limiting steps, all mutants considered could be hydrolyzed by MMP-9. To provide further insights, the hydrolysis mechanism of MMP-2, which has a similar hydrolysis process to that of MMP-9 but with different reaction barriers, is also studied and compared. As a result, this work provides detailed insights into the hydrolysis mechanism of ACPPs by MMP-9 and, thus, also possible insights for the development of new strategies for ACPP-based delivery systems.
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Péptidos de Penetración Celular , Metaloproteinasa 9 de la Matriz , Hidrólisis , Metaloproteinasa 2 de la Matriz , Metaloproteinasa 9 de la Matriz/metabolismo , Simulación de Dinámica MolecularRESUMEN
P-glycoprotein (P-gp), a member of ATP-binding cassette (ABC) transporters, is a multidrug resistance pump. Its promiscuous nature is the main cause of multidrug resistance in cancer cells. P-gp can bind multiple drug molecules simultaneously; however, the binding mechanism is still not clear. Furthermore, the upper limit of the number of substrates that can be accommodated by the binding pocket is not fully understood. In this work, we explore the dynamic process of P-gp binding to multiple substrates by using molecular dynamics (MD) simulations. Our results show that P-gp possesses the ability for simultaneous binding, and that the number of substrates has an upper limit. The accommodating ability of P-gp relates to the size of the binding drugs, and conforms to induced fit theory. In the binding process, the residues 339PHE, 982MET and 986GLN are essential. The pocket of P-gp presents strong flexibility and adaptability features according to the mutation results in this work. Drug molecules tend to gather in the pocket during binding, and interactions between these molecules are beneficial to simultaneous binding. These findings provide new insights into the mechanism of the promiscuous nature of P-gp, and may give us a guideline for inhibiting the process of multidrug resistance.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Antineoplásicos/química , Doxorrubicina/química , Paclitaxel/química , Sorafenib/química , Secuencia de Aminoácidos , Sitios de Unión , Resistencia a Múltiples Medicamentos , Simulación de Dinámica Molecular , Unión Proteica , Conformación Proteica , Electricidad Estática , TermodinámicaRESUMEN
Understanding of drug-carrier interactions is essential for the design and application of metal-organic framework (MOF)-based drug-delivery systems, and such drug-carrier interactions can be fundamentally different for MOFs with or without defects. Herein, we reveal that the defects in MOFs play a key role in the loading of many pharmaceuticals with phosphate or phosphonate groups. The host-guest interaction is dominated by the Coulombic attraction between phosphate/phosphonate groups and defect sites, and it strongly enhances the loading capacity. For similar molecules without a phosphate/phosphonate group or for MOFs without defects, the loading capacity is greatly reduced. We employed solid-state NMR spectroscopy and molecular simulations to elucidate the drug-carrier interaction mechanisms. Through a synergistic combination of experimental and theoretical analyses, the docking conformations of pharmaceuticals at the defects were revealed.
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Adenosina Monofosfato/química , Estructuras Metalorgánicas/química , Nanocápsulas/química , Compuestos Organometálicos/química , Ácidos Ftálicos/química , Composición de Medicamentos , Liberación de Fármacos , Conformación Molecular , Simulación del Acoplamiento Molecular , Organofosfonatos/química , Fosfatos/química , Porosidad , Propiedades de SuperficieRESUMEN
This work describes a novel approach for the synthesis of (-)-epigallocatechin gallate (EGCG) palmitate by a chemical-synthesis method, where the elevated stability of the EGCG derivative is achieved. Various parameters affecting the acylation process, such as the base, solvent, as well as the molar ratio of palmitoyl chloride, have been studied to optimize the acylation procedure. The optimized reaction condition was set as follows: EGCG/palmitoyl chloride/sodium acetate was under a molar ratio of 1:2:2, with acetone as the solvent, and the reaction temperature was 40 °C. Under the optimized condition, the yield reached 90.6%. The EGCG palmitate (PEGCG) was isolated and identified as 4'-O-palmitoyl EGCG. Moreover, the stability of PEGCG under different conditions was proved significantly superior to EGCG. Finally, PEGCG showed better inhibition towards α-amylase and α-glucosidase, which was 4.5 and 52 times of EGCG, respectively. Molecular docking simulations confirmed the in vitro assay results. This study set a novel and practical synthetic approach for the derivatization of EGCG, and suggest that PEGCG may act as an antidiabetic agent.
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Catequina/análogos & derivados , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Palmitatos/farmacología , Polifenoles/química , Té/química , Bacillus licheniformis/enzimología , Catequina/síntesis química , Catequina/química , Catequina/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Ligandos , Simulación del Acoplamiento Molecular , Palmitatos/síntesis química , Palmitatos/química , Saccharomyces cerevisiae/enzimología , alfa-Amilasas/antagonistas & inhibidores , alfa-Amilasas/metabolismo , alfa-Glucosidasas/metabolismoRESUMEN
P-glycoprotein (P-gp, MDR1), one of ATP-binding cassette transporters, may confer tumor cells cross-resistance to chemotherapeutics. A large amount of P-gp inhibitors were designed to inhibit the multidrug resistance (MDR) feature of P-gp. However, no sufficient researches were reported to explore the correlation between binding capacity and drug property by experiment. Without particular drug property found to inhibit the MDR feature of P-gp, the orientation of drug design is indefinite. In this work, 10 representative cancer drugs with various properties are used to bind with P-gp by molecular dynamics simulation. Binding free energy between P-gp and 10 drugs ranges -139 to -253 kJ/mol. It reveals that the promiscuity nature of P-gp is in light of the similar binding free energy in separate P-gp-ligand binding systems. The binding effect of P-gp and drugs correlates well with the size of drugs and has no apparent correlation with the polarity of each drug. The key reason is that van der Waal's interaction occupies most of the total binding free energy, and it is led by the number of atoms in the drugs. Two transmembrane segments (TM6 and TM12) and three types of amino acids (PHE, MET, and GLN) are vital in binding drugs with van der Waal's energy, which evident the influence between binding stability and size of drugs. This work provides the cause and theoretical basis for the promiscuity nature of P-gp.Communicated by Ramaswamy H. Sarma.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Antineoplásicos , Subfamilia B de Transportador de Casetes de Unión a ATP/farmacología , Transportadoras de Casetes de Unión a ATP , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a AntineoplásicosRESUMEN
Communicated by Ramaswamy H. Sarma.
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Sitios de Unión , Metaloproteinasa 2 de la Matriz/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oligopéptidos/química , Aminoácidos/química , Catálisis , Dominio Catalítico , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Modelos Químicos , Mutación , Oligopéptidos/metabolismo , Unión Proteica , Conformación ProteicaRESUMEN
Currently, arginine-rich cell-penetrating peptides (CPPs), due to their little cytotoxicity and high transmembrane efficiency, are considered as one of the important intracellular carriers. Although the mechanism of the transmembrane process for arginine-rich CPPs was proposed, the quantitative correlations and the key factors involved in this process still deserve further investigation. In this study, all-atom molecular dynamics and the umbrella sampling technique were employed to study the arginine-rich CPPs transmembrane process. In the adsorption process of CPPs from solution to the surface of the lipid bilayer, the adsorption free energy (ΔGA) is found to be linearly related to the interaction energy change (ΔEA): ΔGA = 0.0426ΔEA + 36.7, R2 = 0.92. In the CPPs transmembrane process, the transmembrane free energy barrier (ΔGB) is roughly correlated with the corresponding interaction energy change (ΔEB): ΔGB = 0.108ΔEB +135, R2 = 0.73. The multiple salt bridges of guanidinium-PO4 account for 65% of the overall interaction energy, so the increased negative charges of the lipid bilayer or more salt bridges would facilitate CPPs adsorption and transmembrane processes. Also, the increased negative charges of the lipid bilayer would reduce the amount of water to be carried into the pore and further reduce the ΔGB. The peptide backbone would not have a direct impact on transmembrane efficiency. The ΔGB is also found to be related to the length of the pore (L): ΔGB = 46.2L - 31.3, R2 = 0.92, which makes the transmembrane efficiency estimable. This work is expected to deliver an in-depth understanding and help the optimization of CPPs.
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Arginina/química , Péptidos de Penetración Celular/química , Estructura Molecular , Tamaño de la Partícula , Propiedades de Superficie , TermodinámicaRESUMEN
Graphene quantum dots (GQDs) are increasingly being recognized as anti-cancer drug carriers, e.g., doxorubicin delivery, in many experiments. In this work, the structure, thermodynamics and dynamic properties of model drugs (doxorubicin and deoxyadenosine) translocating into a POPC lipid membrane with the assistance of GQDs were investigated via MD simulation and free energy calculation. The simulation results imply that GQD19 can facilitate the permeation of model drugs into the lipid membrane on the nanosecond timescale with less deformation of the cell membrane structure. More importantly, free energy calculations further revealed that the translocation free energy of doxorubicin or deoxyadenosine permeating into the lipid bilayer could be significantly reduced with the assistance of GQD19. Our results suggest that GQDs with appropriate size may assist in the drug delivery process by reducing the translocation free energy permeating into the biomembrane. These results may promote the molecular design and application of GQD-based drug delivery systems.