共查询到20条相似文献,搜索用时 46 毫秒
1.
Abbreviations ADME absorption, distribution, metabolism, and excretion MMGB/SA molecular mechanics generalized born surface area IFD induced fit docking RTK receptor tyrosine kinase NSCLC non-small-cell lung cancer ATP adenosine triphosphate OPLS optimized potential for liquid stimulation RMSD root mean square deviation HTVS high-throughput virtual screening SP standard precision XP extra precision OPLS-AA optimized potential for liquid stimulation-all atom MD molecular simulation MME molecular mechanics energies SGB surface generalized born POPC membrane 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine membrane PDB Protein Data Bank DDR1 discoidin domain receptor 1 DDR2 discoidin domain receptor 2 DDRs discoidin domain receptors ECM extracellular matrix TIP4P transferable intermolecular potential 4 point NPT constant particle number, pressure and temperature RMSF root mean square fluctuation Communicated by Ramaswamy H. Sarma 相似文献
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Abbreviations C catechin ECG epicatechin gallate EGCG Epigallocatechin gallate A Adenine C cytosine G Guanine U uracil FTIR Fourier transform infrared Communicated by Ramaswamy H. Sarma 相似文献
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Abbreviations SAHA suberoylanilide hydroxamic acid EhHDAC Histone Deacetylase from Entamoeba histolytica Rg Radius of gyration RMSD root-mean-square deviation RMSF root-mean-square fluctuation MDS molecular dynamics simulation VMD Visual Molecular Dynamics NAMD Nanoscale Molecular Dynamics PBC periodic boundary conditions PME Particle Mesh Ewald 3D three-dimensional Cα alpha carbon FDA Food and Drug Administration ns nanoseconds GPU CUDA Graphics Processing Unit Compute Unified Device Architecture Communicated by Ramaswamy H. Sarma 相似文献
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Abbreviations COM center of mass distance MD molecular dynamics MM-PBSA Molecular Mechanics Poisson–Boltzmann Surface Area Nb nanobody PlGF placenta growth factor Rg radius of gyration RMSD root mean-square deviation SASA solvent-accessible surface area VEGF vascular endothelial growth factor 相似文献
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AbstractComplete functional annotations of proteins are essential to understand the role and mechanisms in pathogenesis. Aminoglycoside nucleotidyltransferases are the subclasses of aminoglycosides modifying enzymes conferring resistance to organisms. Insight into the structural and functional understanding of nucleotidyltransferase family protein provides vital information to combat pathogenesis. Phylogenetic analysis is employed to identify the evolutionary significance and common motif’s present among the homologs of nucleotidyltransferase family protein. Structure, sequence based approaches and molecular docking were implemented to predict the exact function of the protein. Wide distribution of the nucleotidyltransferase family protein in gram-positive and gram-negative organisms are evidenced from phylogenetic analysis. Five common motifs were present in all the homolog’s of nucleotidyltransferase family protein. Sequence-structure based functional annotations predicts that the targeted protein function as ATP-Mg dependent streptomycin adenylyltransferase. Structural comparisons and docking studies correlate well with the identified function. The complete function of nucleotidyltransferase family protein was identified as Streptomycin adenylyltransferase and it could be targeted as a potential therapeutic target to overcome antibiotic resistance.Communicated by Ramaswamy H. Sarma Abbreviations AAC aminoglycoside acetyltransferases AME aminoglycoside modifying enzyme ANT aminoglycoside nucleotidyltransferases APH aminoglycoside phosphotransferases ATP adenosine triphosphate CASTp computer atlas and surface topography of proteins DUF domains of unknown function Glide grid-based ligand docking with energetic HMM hidden Markov model MAST motif alignment and search tool MEGA molecular evolutionary genetics analysis MEME multiple Em for motif elicitation MSA multiple sequence alignment NMP nucleoside monophosphate NTP nucleoside triphosphate NT nucleotidyltransferase OPLS optimized potential for liquid simulation XP extra precision 相似文献
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Ecology and evolution Agricultural education Evolution and education Education division elections ISII in Europe Tree project Science teaching scholarship Biology of terrestrial arthropods A microscopied museum 相似文献
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AbstractPhosphorylation of protein is critical for various cell processes, which preferentially happens in intrinsically disordered proteins (IDPs). How phosphorylation modulates structural ensemble of disordered peptide remains largely unexplored. Here, using replica exchange molecular dynamics (REMD) and Markov state model (MSM), the conformational distribution and kinetics of p53 N-terminal transactivation domain (TAD) 2 as well as its dual-site phosphorylated form (pSer46, pThr55) were simulated. It reveals that the dual phosphorylation does not change overall size and secondary structure element fraction, while a change in the distribution of hydrogen bonds induces slightly more pre-existing bound helical conformations. MSM analysis indicates that the dual phosphorylation accelerates conformation exchange between disordered and order-like states in target-binding region. It suggests that p53 TAD2 after phosphorylation would be more apt to bind to both the human p62 pleckstrin homology (PH) domain and the yeast tfb1?PH domain through different binding mechanism, where experimentally it exhibits an extended and α-helix conformation, respectively, with increased binding strength in both complexes. Our study implies except binding interface, both conformation ensemble and kinetics should be considered for the effects of phosphorylation on IDPs. Abbreviations IDPs intrinsically disordered proteins REMD replica exchange molecular dynamics MSM Markov state model TAD transactivation domain PH pleckstrin homology PRR proline-rich region DBD DNA-binding domain TET Tetramerization domain REG regulatory domain MD molecular dynamics PME particle-mesh Ewald TICA time-lagged independent component analysis CK Chapman–Kolmogorov GMRQ generalized matrix Rayleigh quotient SARW self-avoiding random walk KID kinase-inducible domain MFPT mean first passage time DSSP definition of secondary structure of proteins RMSD root mean square deviation Rg radius of gyration Ree end to end distance Communicated by Ramaswamy H. Sarma 相似文献
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Abbreviations HA Hemagglutinin MD Molecular Dynamics MM-PBSA Molecular Mechanics Poisson–Boltzmann Surface Area NA Neuraminidase NAMD Nanoscale Molecular Dynamic Simulation PMEMD Particle Mesh Ewald Molecular Dynamics RMSD Root-Mean-Square Deviation RMSF Root-Mean-Square Fluctuation SIA sialic acid VMD Visual Molecular Dynamics Communicated by Ramaswamy H. Sarma 相似文献
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AbstractBy having knowledge about the characteristics of protein interaction interfaces, we will be able to manipulate protein complexes for therapies. Dimer state is considered as the primary alphabet of the most proteins’ quaternary structure. The properties of binding interface between subunits and of noninterface region define the specificity and stability of the intended protein complex. Considering some topological properties and amino acids’ affinity for binding in interfaces of protein dimers, we construct the interface-specific recurrence plots. The data obtained from recurrence quantitative analysis, and accessibility-related metrics help us to classify the protein dimers into four distinct classes. Some mechanical properties of binding interfaces are computed for each predefined class of the dimers. The computed mechanical characteristics of binding patch region are compared with those of nonbinding region of proteins. Our observations indicate that the mechanical properties of protein binding sites have a decisive impact on determining the dimer stability. We introduce a new concept in analyzing protein structure by considering mechanical properties of protein structure. We conclude that the interface region between subunits of stable dimers is usually mechanically softer than the interface of unstable protein dimers. Abbreviations AAB average affinity for binding ANM anisotropic network model APC affinity propagation clustering ASA accessible surface area CCD inter residues distance CSC complex stability code DM distance matrix ΔG diss PISA-computed dissociation free energy GNM Gaussian normal mode analysis NMA normal mode analysis PBP protein binding patch PISA proteins, interfaces, structures and assemblies rASA relative accessible area in respect to unfolded state of residues RM recurrence matrix rP relative protrusion RP recurrence plot RQA recurrence quantitative analysis SEM standard error of mean Communicated by Ramaswamy H. Sarma 相似文献
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AbstractThe chromosome numbers of five species belonging to the Jubulae have been described, and are as follows:Lejeuneaceae Cololejeunea cf. dissita, n = 9. Arehilejeunea autoiea Vanden Berghen, n=9. Caudalejeunea hanningtonii (Mitt.) Schiffn., n =9. Mastigolejeunea florea (Mitt.) Steph., n=9.Frullaniaceae Frullania spongiosa Steph., female, n = 9. F. spongiosa Steph., male, n=8.The author wishes to thank Dr E. W. Jones for assistance in identifications, especially with Cololejeunea cf. dissita. 相似文献
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The metastatic spread of tumors is a well-coordinated process in which different types ofcancers tend to form metastases in defined organs. The formation of site-specific metastasesrequires full compatibility between the intrinsic properties of the tumor cells and the tumormicroenvironment. It was recently found that chemokines which are expressed in specific locipromote the adhesion, migration and invasion of tumor cells that express the correspondingreceptor/s. Of the different members of the family, the CXCL12 chemokine and its cognateCXCR4 receptor are the prototypes of this process, although other members of the family (e.g.CCR7 and CCR10) also play a role in determination of the metastatic spread. This commentaryaddresses the fundamental roles of chemokines and their receptors in site-specific metastasis,with emphasis on CXCL12-CXCR4. The article also describes some of the efforts that wereperformed thus far in order to identify the intracellular components involved in this process. Thefocus is put on the roles played by proteins that regulate adhesion and migration of tumor cellsin response to CXCL12, including mainly Focal Adhesion Kinase, Pyk2/RAFTK and members ofthe Rho family of GTPases (RhoA, Rac, Cdc42). This is followed by discussion of openquestions that need to be addressed in future research, and of the potential therapeuticimplications of the findings that are available to date in this field. 相似文献
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The Mediterranean evergreen vegetation of Sicily, comprised in the belt of the Quercetea ilicis, occupies a large part of the island. Human intervention (cutting, fire, pasture) has brought about a degradation of the natural vegetation. This study is based on our phytosociological research of the Quercetea ilicis belt on Sicily. With the ‘habitat comparison’ method, the dynamical relations between the different vegetation units have been defined. We distinguish the following stages, with reference to their vegetation structure:
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a herbaceous stage formed by steppic vegetation, preceded by various types of nitrophilous-ruderal vegetation on abandoned fields;
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a garrigue stage dominated by half-shrubs;
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a macquis stage with various distinct plant communities, four communities being important in regressive successions, and three in progressive ones;
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a woodland and shrub-woodland stage with three different substages: pre-existent forests, present woodlands, and woodlands which tend towards the final, stable stage of vegetation (potential natural vegetation).
The dynamic relationships both in progressive and regressive successions have been synthesized in a scheme. In this scheme we have shown the main stages of the vegetation in their dynamics and we have constructed different series of vegetation types in two altitudinal belts, which are determined by varying environmental conditions of today. The results also show that in some cases the progressive series follow different pathways than the regressive series, and the final stage of the progressive series is different from the original vegetation. 相似文献
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AbstractPyrazinamide (PZA) is an important component of first-line anti-tuberculosis (anti-TB) drugs. The anti-TB agent is activated into an active form, pyrazinoic acid (POA), by Mycobacterium tuberculosis (MTB) pncA gene encoding pyrazinamidase (PZase). The major cause of PZA-resistance has been associated with mutations in the pncA gene. We have detected several novel mutations including V131F, Q141P, R154T, A170P, and V180F (GeneBank Accession No. MH461111) in the pncA gene of PZA-resistant isolates during PZA drug susceptibility testing followed by pncA gene sequencing. Here, we investigated molecular mechanism of PZA-resistance by comparing the results of experimental and molecular dynamics. The mutants (MTs) and wild type (WT) PZase structures in apo and complex with PZA were subjected to molecular dynamic simulations (MD) at the 40?ns. Multiple factors, including root mean square deviations (RMSD), binding pocket, total energy, dynamic cross correlation, and root mean square fluctuations (RMSF) of MTs and WT were compared. The MTs attained a high deviation and fluctuation compared to WT. Binding pocket volumes of the MTs, were found, lower than the WT, and the docking scores were high than WT while shape complementarity scores were lower than that of the WT. Residual motion in MTs are seemed to be dominant in anti-correlated motion. Mutations at locations, V131F, Q141P, R154T, A170P, and V180F, might be involved in the structural changes, possibly affecting the catalytic property of PZase to convert PZA into POA. Our study provides useful information that will enhance the understanding for better management of TB. Abbreviations DST drug susceptibility testing Δelec electrostatic energy LJ Lowenstein–Jensen medium MGIT mycobacterium growth indicator tubes MTs mutants MD molecular dynamic simulations MTB Mycobacterium tuberculosis NALC–NaOH N-acetyl-l-cysteine–sodium hydroxide NIH National Institutes of Health NPT amount of substance (N), pressure (P) temperature (T) NVT moles (N), volume (V) temperature (T) PZase pyrazinamidase Δps polar solvation energy PTRL Provincial Tuberculosis Reference Laboratory RMSD root mean square deviations RMSF root mean square fluctuations ΔSASA solvent accessible surface area energy TB tuberculosis GTotal total binding free energy ΔvdW Van der Waals energy WT wild type Communicated by Ramaswamy H. Sarma 相似文献
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Persistent inflammation within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic inflammation in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary inflammation and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD chronic obstructive pulmonary disease CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor 相似文献
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AbstractThe human HMGB1 gene mutations have a major impact on several immune-related diseases and cancer. The detrimental effect of non-synonymous mutations of HMGB1 has not been investigated yet, hence the present study aims to examine single nucleotide polymorphisms and their implications on the structure-function of human HMGB1. The multifaceted HMGB1 protein acts as pleiotropic cytokine and regulates essential genes for coordinated cellular functions. The mutational effect on HMGB1 was analyzed by sequence-based homology methods, supervised learning methods, and structure-based methods. The study identified 58 non-synonymous mutations in human HMGB1, out of which only 2 mutations; R10T (rs61742222) and F103C (rs61733675) were classified as the SNPs with highest deleterious and disease-causing mutants. The effect of these mutations in structure of HMGB1 was scrutinized and the R10T mutant found to have a distinct structural behaviour in the B-box domain. In addition, R10T mutant predicted that it affects the MoRF function of HMGB1 and it could disrupt the DNA binding or/and protein partner interaction activity by HMGB1. F103C mutation takes place at the TLR binding and cytokine inducing region of HMGB1, hence it could affect the protein binding activity which involves in many cellular signaling. The study identified potent mutations R10T (a cancer-causing somatic mutation) and F103C (a novel mutation) and these mutations either directly or indirectly hinder DNA binding activity and TLR and cytokine binding of HMGB1. These findings will help in understanding the molecular basis of these promising mutations and functional role of human HMGB1 in cancer and immunological diseases. Abbreviations AGER Advanced glycosylation end product-specific receptor CXCL Chemokine (C-X-C motif) ligand dbSNP The single nucleotide polymorphism database HMGB1 High mobility group box 1 LINCS LINear Constraint Solver MDS Molecular dynamics simulation MoRF Molecular recognition features NPT Number of particle, Pressure and Temperature NVT Number of particle, Volume and Temperature nsSNP Non-synonymous SNP PBC Partial boundary condition PCA Principal component analysis PME Partial mesh Ewald RMSD Root mean square deviation RMSF Root mean square fluctuation SNP Single nucleotide polymorphism SPC Single-point charge TLR Toll-like receptor UTR Un-translated Region Communicated by Ramaswamy H. Sarma 相似文献
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AbstractN-methyl-D-aspartate receptors (NMDARs), a class of ligand-gated ion channels, are involved in non-selective cation transport across the membrane. These are contained in glutamatergic synapse and produce excitatory effects leading to synaptic plasticity and memory function. GluN1-GluN2B, a subtype of NMDAR(s), has significant role in neurodegeneration, amyloid β (Aβ) induced synaptic dysfunction and loss. Thus, targeting and inhibiting GluN1-GluN2B may be effective in the management of neurodegenerative diseases including Alzheimer’s disease. In the present study, ligand and structure-based approaches were tried to identify the inhibitors. The pharmacophore, developed from co-crystallised ifenprodil, afforded virtual hits, which were further subjected through drug likeliness and PAINS filters to remove interfering compounds. Further comprehensive docking studies, free energy calculations and ADMET studies resulted in two virtual leads. The leads, ZINC257261614 and ZINC95977857 displayed good docking scores of ?12.90 and ?12.20?Kcal/mol and free binding energies of ?60.83 and ?61.83?Kcal/mol, respectively. The compounds were having acceptable predicted ADMET profiles and were subjected to molecular dynamic (MD) studies. The MD simulation produced stable complexes of these ligands with GluN1-GluN2B subunit having protein and ligand RMSD in acceptable limit. Abbreviations AD Alzheimer's disease ADME Absorption distribution metabolism and excretion ATD Amino terminal domain BBB Blood-brain barrier CNS Central nervous system CREB cAMP response element binding protein CTD Carboxy-terminal domain Glu Glutamate GMQE Global model quality estimation HTVS High throughput virtual screening HIA Human intestinal absorption LGA Lamarckian genetic algorithm MD Molecular dynamics MM-GBSA Molecular mechanics, the Generalised Born model for Solvent Accessibility NMDAR N-methyl-D-aspartate receptors PAINS Pan assay interference compounds RMSD Root-mean square deviation RMSF Root-mean-square fluctuation SMARTS SMILES arbitrary target specification SP standard precision XP extra precision Communicated by Ramaswamy H. Sarma 相似文献
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AbstractOsteoarthritis (OA) is the most common form of arthritis with no available disease-modifying treatments, and is a major cause of disability. Matrix metalloproteinase 13 (MMP-13) is vital for OA progression and thus, inhibition of MMP-13 is an effective strategy to treat OA. Since the past few decades, drug repurposing has gained substantial popularity worldwide as a time- and cost-effective approach to find new indications for the existing drugs. Therefore, more than 40 X-ray co-crystal structures of the human MMP-13 with bound inhibitors are investigated to gain the structural insights such as conserved direct interactions with binding site residues, namely Ala-238, Thr-245 and Thr-247. Afterwards, enrichment study using active and decoy set of ligands revealed three MMP-13 structures (PDB-IDs: 1XUC, 3WV1 and 5BPA) with optimal enrichment performance. Docking-based screening of existing drugs against the three crystal structures followed by binding free-energy calculation suggested drugs namely eltrombopag, cilostazol and domperidone as potential MMP-13 inhibitors that need further experimental validation. These insights may serve as a potential starting point of further experimental validation and structure-based drug design/repurposing of MMP-13 inhibitors for the treatment of OA. Abbreviations 2D two-dimensional 3D three-dimensional FDA Food and Drug Administration MM-GBSA Molecular Mechanics Generalized Born Surface Area MMPs matrix metalloproteinases MMP-13 matrix metalloproteinase 13 NMR nuclear magnetic resonance OA osteoarthritis PDB Protein Data Bank PDB-ID Protein Data Bank ID PLIP protein–ligand interaction profiler ROC receiver operating characteristic, RMSD root mean square deviation Communicated by Ramaswamy H. Sarma 相似文献
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