Influence of gold-bipyridyl derivants on aggregation and disaggregation of the prion neuropeptide PrP106-126.

Metal complexes can effectively inhibit the aggregation of amyloid peptides, such as Aß, human islet amyloid polypeptide, and prion neuropeptide PrP106-126. Gold (Au) complexes exhibited better inhibition against PrP106-126 aggregation, particularly the Au-bipyridyl (bpy) complex; however, the role of different ligand configurations remains unclear. In the present study, three derivants of Au-bpy complexes, namely, [Au(Me2bpy)Cl2]Cl, [Au(t-Bu2bpy)Cl2]Cl, and [Au(Ph2bpy)Cl2]Cl, were investigated to determine their influence on the aggregation and disaggregation of PrP106-126. The steric and aromatic effects of the ligand resulted in enhanced binding affinity. Inhibition was significantly affected by a large ligand. The neurotoxicity of the SH-SY5Y cells induced by PrP106-126 was reduced by the three Au-bpy derivants. However, the disaggregation ability was not in accordance with the results obtained for selected complexes during inhibition, suggesting a different mechanism of interaction between gold complexes and PrP106-126. The key peptide residues contributed to both the inhibition and disaggregation capabilities through the metal coordination and the hydrophobic interaction with the metal complexes. Thus, understanding the aggregation mechanism of the prion peptide would be helpful in designing novel metal-based drugs against amyloid fibril formation.

Regulation of aggregation behavior and neurotoxicity of prion neuropeptides by platinum complexes.

Prion diseases belong to a group of infectious, fatal neurodegenerative disorders. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion disease pathology. PrP106-126 resembles PrP(Sc) in some physicochemical and biological characteristics, such as apoptosis induction in neurons, fibrillar formation, and mediation of the conversion of native cellular PrP(C) to PrP(Sc). Numerous studies have been conducted to explore the inhibiting methods on the aggregation and neurotoxicity of prion neuropeptide PrP106-126. We showed that PrP106-126 aggregation, as assessed by fluorescence assay and atomic force microscopy, is inhibited by platinum complexes cisplatin, carboplatin, and Pt(bpy)Cl2. ESI-MS and NMR assessments of PrP106-126 and its mutant peptides demonstrate that platinum complexes bind to the peptides in coordination and nonbonded interactions, which rely on the ligand properties and the peptide sequence. In peptides, methionine residue is preferred as a potent binding site over histidine residue for the studied platinum complexes, implying a typical thiophile characteristic of platinum. The neurotoxicity induced by PrP106-126 is better inhibited by Pt(bpy)Cl2 and cisplatin. Furthermore, the ligand configuration contributes to both the binding affinity and the inhibition of peptide aggregation. The pursuit of novel platinum candidates that selectively target prion neuropeptide is noteworthy for medicinal inorganic chemistry and chemical biology.

Stereochemistry of 4-hydroxyproline affects the conformation of conopeptides.

The cis/trans isomerization of 4-hydroxyproline is shown to remarkably affect the conformation of conopeptides with or without disulfide bonds.

Studies on the conformational change of adsorbed BSA onto a moderately hydrophobic surface at different denaturant concentrations and surface coverages.

This paper is aimed at investigating the conformational change of denatured bovine serum albumin (BSA) in combination with thermodynamic functions and their fractions, adsorption isotherms, Fourier transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC). Microcalorimetric measurements of displacement adsorption enthalpies DeltaH of denatured BSA (by guanidine hydrochloride (GuHCl)) adsorbed onto a moderately hydrophobic surface (PEG-600) from solutions were carried out. The contents of secondary structure elements of BSA in solutions and in the adsorbed state were determined by FTIR and the thermal stability of adsorbed BSA was measured by DSC. The adsorption thermodynamic functions DeltaH, DeltaS, DeltaG, and their fractions were calculated based on the thermodynamics of the stoichiometric displacement theory for adsorption (SDT-A) and adsorption isotherms. The results showed that the surface can provide energy to denatured BSA and make it gain a more ordered conformation with GuHCl concentration increment. At a given GuHCl concentration, although the ordered secondary structure of adsorbed BSA molecules decreased, their tertiary structure may be more perfect with surface coverage increment. The thermodynamic analysis of four subprocesses associated with adsorption also confirmed the increment of conformational gain.

Molecular dynamics simulation of a carboxy murine neuroglobin mutated on the proximal side: heme displacement and concomitant rearrangement in loop regions.

Neuroglobin, a member of vertebrate globin family, is distributed primarily in the brain and retina. Considerable evidence has accumulated regarding its unique ligand-binding properties, neural-specific distribution, distinct expression regulation, and possible roles in processes such as neuron protection and enzymatic metabolism. Structurally, neuroglobin enjoys unique features, such as bis-histidyl coordination to heme iron in the absence of exogenous ligand, heme orientational heterogeneity, and a heme sliding mechanism accompanying ligand binding. In the present work, molecular dynamics (MD) simulations were employed to reveal functional and structural information in three carboxyl murine neuroglobin mutants with single point mutations F106Y, F106L and F106I, respectively. The MD simulation indicates a remarkable proximal effect on detectable displacement of heme and a larger tunnel in the protein matrix. In addition, the mutation at F106 confers on the CD region a very sensitive mobility in all three model structures. The dynamic features of neuroglobin demonstrate rearrangement of the inner space and highly active loop regions in solution. These imply that the conserved residue at the G5 site plays a key role in the physiological function of this unusual protein.