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91.
We report here a comparative study of the molecular conformational energy landscape generated using the mutually orthogonal Latin squares (MOLS) method, molecular dynamics (MD), and Monte Carlo (MC) simulation. The MOLS method, as described earlier from our laboratory, uses an experimental design technique to rapidly and exhaustively sample the low energy conformations of a molecule. MD and MC simulations have been used to perform similar tasks. In the comparison reported here, the three methods were applied to a pair of neuropeptides, namely Met- and Leu-enkephalin. A set of 1500 conformations of these enkephalins were generated using these methods with CHARMM22 force field, and the resulting samples were analyzed to determine the extent and nature of coverage of the conformational space. The results indicate that the MOLS method samples a larger number of possible conformations and identifies conformations closer to the experimental structures than the MD and MC simulations. 相似文献
92.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and characterized by the formation of multiple fluid-filled cysts in the kidneys. It is believed that environmental factors may play an important role in the disease progression. However, the molecular identity of autocrine/paracrine factors influencing cyst formation is largely unknown. In this study, we identified transforming growth factor-β2 (TGF-β2) secreted by normal human kidney (NHK) and ADPKD cells as an inhibitor of cystogenesis in 3D culture system using ADPKD cells from human kidneys. TGF-β2 was identified in conditioned media (CM) of NHK and ADPKD cells as a latent factor activated by heat in vitro. While all TGF-β isoforms recombinant proteins (TGF-β1, -β2, or -β3) displayed a similar inhibitory effect on cyst formation, TGF-β2 was the predominant isoform detected in CM. The involvement of TGF-β2 in the suppression of cyst formation was demonstrated by using a TGF-β2 specific blocking antibody and a TGF-β receptor I kinase inhibitor. TGF-β2 inhibited cyst formation by a mechanism other than activation of p38 mitogen-activated protein (MAP) kinase that mediated cell death in ADPKD cells. Further, we found that TGF-β2 modulated expression of various genes involved in cell-cell and cell-matrix interactions and extracellular matrix proteins that may play a role in the regulation of cystogenesis. Collectively, our results suggest that TGF-β2 secreted by renal epithelial cells may be an inhibitor of cystogenesis influencing the progression of ADPKD. 相似文献
93.
Jayaraman M Kodali R Sahoo B Thakur AK Mayasundari A Mishra R Peterson CB Wetzel R 《Journal of molecular biology》2012,415(5):881-899
The 17-amino-acid N-terminal segment (htt(NT)) that leads into the polyglutamine (polyQ) segment in the Huntington's disease protein huntingtin (htt) dramatically increases aggregation rates and changes the aggregation mechanism, compared to a simple polyQ peptide of similar length. With polyQ segments near or above the pathological repeat length threshold of about 37, aggregation of htt N-terminal fragments is so rapid that it is difficult to tease out mechanistic details. We describe here the use of very short polyQ repeat lengths in htt N-terminal fragments to slow this disease-associated aggregation. Although all of these peptides, in addition to htt(NT) itself, form α-helix-rich oligomeric intermediates, only peptides with Q(N) of eight or longer mature into amyloid-like aggregates, doing so by a slow increase in β-structure. Concentration-dependent circular dichroism and analytical ultracentrifugation suggest that the htt(NT) sequence, with or without added glutamine residues, exists in solution as an equilibrium between disordered monomer and α-helical tetramer. Higher order, α-helix rich oligomers appear to be built up via these tetramers. However, only htt(NT)Q(N) peptides with N=8 or more undergo conversion into polyQ β-sheet aggregates. These final amyloid-like aggregates not only feature the expected high β-sheet content but also retain an element of solvent-exposed α-helix. The α-helix-rich oligomeric intermediates appear to be both on- and off-pathway, with some oligomers serving as the pool from within which nuclei emerge, while those that fail to undergo amyloid nucleation serve as a reservoir for release of monomers to support fibril elongation. Based on a regular pattern of multimers observed in analytical ultracentrifugation, and a concentration dependence of α-helix formation in CD spectroscopy, it is likely that these oligomers assemble via a four-helix assembly unit. PolyQ expansion in these peptides appears to enhance the rates of both oligomer formation and nucleation from within the oligomer population, by structural mechanisms that remain unclear. 相似文献
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97.
Mild oxidation promotes and advanced oxidation impairs remodeling of human high-density lipoprotein in vitro 总被引:1,自引:0,他引:1
High-density lipoproteins (HDLs) prevent atherosclerosis by removing cholesterol from macrophages and by exerting antioxidant and anti-inflammatory effects. Oxidation is thought to impair HDL functions, yet certain oxidative modifications may be advantageous; thus, mild oxidation reportedly enhances cell cholesterol uptake by HDL whereas extensive oxidation impairs it. To elucidate the underlying energetic and structural basis, we analyzed the effects of copper and hypochlorite (which preferentially oxidize lipids and proteins, respectively) on thermal stability of plasma spherical HDL. Circular dichroism, light scattering, calorimetry, gel electrophoresis, and electron microscopy showed that mild oxidation destabilizes HDL and accelerates protein dissociation and lipoprotein fusion, while extensive oxidation inhibits these reactions; this inhibition correlates with massive protein cross-linking and with lipolysis. We propose that mild oxidation lowers kinetic barriers for HDL remodeling due to diminished apolipoprotein affinity for lipids resulting from oxidation of methionine and aromatic residues in apolipoproteins A-I and A-II followed by protein cross-linking into dimers and/or trimers. In contrast, advanced oxidation inhibits protein dissociation and HDL fusion due to lipid redistribution from core to surface upon lipolysis and to massive protein cross-linking. Our results help reconcile the apparent controversy in the studies of oxidized HDL and suggest that mild oxidation may benefit HDL functions. 相似文献
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99.
A kinetic study of the interaction of bivalent and monovalent sugar ligands with a lectin was undertaken with the aid of surface
plasmon resonance (SPR) method. The study involved a series of bivalent α-d-mannopyranoside containing sugar ligands, with systematic variation in the distance between the sugar ligands. The detailed
kinetic studies showed that bivalent ligands underwent a faster association (k
on) and a slower dissociation (k
off) of the ligand–lectin complexes, in comparison to the monovalent ligand–lectin complexes. The kinetic constants were complemented
further by assessing the thermodynamic parameters with the aid of isothermal titration calorimetry (ITC). The initiation of
cross-linking of ligand–lectin interactions emerge from the early stages of the complexation. The dynamic light scattering
(DLS) and the transmission electron microscopy (TEM) techniques allowed judging the sizes and morphologies of the complex
in the solution and solid states, respectively. 相似文献
100.
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, one subtype in the family of ionotropic glutamate receptors, are the main receptors responsible for excitatory signaling in the mammalian central nervous system. Previous studies utilitizing the isolated ligand binding domain of these receptors have provided insight into the role of specific ligand-protein interactions in mediating receptor activation. However, these studies relied heavily on the partial agonist kainate, in which the alpha-amine group is constrained in a pyrrolidine ring. Here we have studied a series of substituted and unsubstituted willardiines with primary alpha-amine groups similar to that of the full agonist glutamate whose activation can be varied depending on the size of the substituent. The specific ligand-protein interactions in the mechanism of partial agonism in this subtype were investigated using vibrational spectroscopy, and the large-scale conformational changes in the ligand binding domain were studied with fluorescence resonance energy transfer (FRET). These investigations show that the strength of the interaction at the alpha-amine group correlates with the extent of cleft closure and extent of activation, with the agonist of higher efficacy showing larger cleft closure and stronger interactions at this group, suggesting that this is one of the mechanisms by which the agonist controls receptor activation. 相似文献