Dissociation Of Amyloid Fibrils Research Articles

Picosecond dissociation of amyloid fibrils with infrared laser: A nonequilibrium simulation study.

Recently, mid-infrared free-electron laser technology has been developed to dissociate amyloid fibrils. Here, we present a theoretical framework for this type of experiment based on laser-induced nonequilibrium all-atom molecular dynamics simulations. We show that the fibril is destroyed due to the strong resonance between its amide I vibrational modes and the laser field. The effects of laser irradiation are determined by a balance between fibril formation and dissociation. While the overall rearrangements of the fibril finish over short time scales, the interaction between the peptides and the solvent continues over much longer times indicating that the waters play an important role in the dissociation process. Our results thus provide new insights into amyloid fibril dissociation by laser techniques and open up new venues to investigate the complex phenomena associated with amyloidogenesis.

Both the Formation and Polyphenol-Induced Dissociation of Various Amyloid Fibrils are Accompanied by ROS Formation

Fibrillization of amyloid polypeptides is accompanied by formation of reactive oxygen species (ROS), which, in turn, is assumed to further promote amyloid-related pathologies. Different polyphenols, all of which are established antioxidants, cause dissociation of amyloid fibrils. In this study we address the latter, poorly understood process. Specifically, we have investigated the dissociation of Aβ42 fibrils by six different polyphenols, using electron microscopy and spectrofluorimetric analysis. Simultaneously, we have monitored the production of ROS using electron spin resonance (ESR) and the commercially available peroxide assay kit. Using the same methods, we found that curcumin, one of the most potent destabilizing agents of Aβ42, induces dissociation of fibrils of other amyloid polypeptides [Aβ40, Aβ42Nle35, islet amyloid polypeptide and a fragment of α-synuclein].When the solution contained traces of transition metal, all the dissociation reactions were accompanied by ROS formation, independent of the presence of a methionine residue. Kinetic studies show that the formation of ROS lags behind dissociation, indicating that if casual relationship exists between these two processes, then ROS formation may be considered a consequence and not a cause of dissociation.Understanding of our results and of their implications requires further research.

Polyphenol-induced dissociation of various amyloid fibrils results in a methionine-independent formation of ROS

Fibrillization of amyloid polypeptides is accompanied by formation of reactive oxygen species (ROS), which, in turn, is assumed to further promote amyloid-related pathologies. Different polyphenols, all of which are established antioxidants, cause dissociation of amyloid fibrils. This study addresses the latter, poorly understood process. Specifically, we have investigated the dissociation of Aβ 42 fibrils by six different polyphenols, using electron microscopy and spectrofluorometric analysis. Simultanously, we have monitored the production of ROS using electron spin resonance (ESR) and the commercially available peroxide assay kit. Using the same methods we found that curcumin, one of the most potent destabilizing agents of Aβ 42, induced dissociation of fibrils of other amyloid polypeptides [Aβ 40, Aβ 42Nle35, islet amyloid polypeptide and a fragment of α-synuclein]. When the solution contained traces of transition metal, all the dissociation reactions were accompanied by ROS formation, independent of the presence of a methionine residue. Kinetic studies show that the formation of ROS lags behind dissociation, indicating that if casual relationship exists between these two processes, then ROS formation may be considered a consequence and not a cause of dissociation. These findings open new avenues in amyloid research that will be required to gain further understanding of our results and of their implications.

Protein unfolding, amyloid fibril formation and configurational energy landscapes under high pressure conditions

High hydrostatic pressure induces conformational changes in proteins ranging from compression of the molecules to loss of native structure. In this tutorial review we describe how the interplay between the volume change and the compressibility leads to pressure-induced unfolding of proteins and dissociation of amyloid fibrils. We also discuss the effect of pressure on protein folding and free energy landscapes. From a molecular viewpoint, pressure effects can be rationalised in terms of packing and hydration of proteins.

Thermodynamics of Aβ(1−40) Amyloid Fibril Elongation

We describe herein the characterization of the equilibrium point for A beta(1-40) amyloid fibril elongation in phosphate-buffered saline at 37 degrees C. Seeded fibril elongation progresses rapidly to a reproducible end point of 0.7-1.0 microM unpolymerized monomeric peptide. This remaining monomeric material is functional, since after concentration it supports fibril elongation. Incubation of fibrils in the same buffer results in dissociation to a final monomer concentration in the same range. This robust C(r) value is equivalent to the A beta(1-40) fibril dissociation constant, Kd. The fact that a similar value for Kd is obtained from a ratio of dissociation and elongation rate constants further supports the view that these values are associated with a position of dynamic equilibrium and therefore are related to free energies of amyloid fibril elongation. The C(r) value reported here for wild-type A beta(1-40) fibrils corresponds to a free energy of fibril elongation of about -9 kcal/mol, a value similar to free energies of folding for small globular proteins. Elongation and dissociation of amyloid fibrils from point mutants of A beta(1-40) also yield C(r) values, different for different mutants, that reflect stabilizing/destabilizing effects. Interestingly, assembly of A beta(1-40) fibrils in the presence of a saturating concentration of the amyloid dye thioflavin T does not measurably affect fibril stability, in contrast to the commonly observed stabilization of globular proteins by ligand binding. The ability to quantify and compare amyloid fibril thermodynamic stabilities makes it possible to include fibrils, and potentially other aggregates, in quantitative descriptions of protein folding landscapes.